Pharmaceutical compositions for minocycline

ABSTRACT

The present application relates to a method of orally administering once daily tablet of minocycline to a subject in need thereof, wherein said tablet is substantially free of lactose. The present application also relates to processes for preparing said once daily tablet of minocycline that provides reduced stock keeping units with improved inventory by supplying multiple doses of minocycline in single tablet.

RELATED APPLICATIONS

This application claims priority from U.S. patent application Ser. No.15/093,673, filed Apr. 7, 2016 and Indian Provisional Application No.1815/CHE/2015, filed Apr. 7, 2015.

TECHNICAL FIELD

The present invention relates to a composition comprising minocycline, amethod of orally administering a once daily tablet of minocycline to asubject in need thereof, and a processes for preparing the tabletthereof.

BACKGROUND

Minocycline is a semi synthetic derivative of tetracycline,[4S-(4α,4aα,5aα,12aα)]-4,7-Bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide.The Orange Book of USFDA lists various dosage forms of minocyclinehydrochloride such as immediate release (IR) tablets, capsules, andextended release (ER) tablets, indicated for the treatment of onlyinflammatory lesions of non-nodular moderate to severe acne vulgaris insubjects 12 years of age and older. Intravenous injection is availablefor the treatment of infections caused by various bacteria.Additionally, extended release powder for dental applications isavailable for treatment as an adjunct to scaling and root planningprocedures for reduction of pocket depth in subjects with adultperiodontitis.

Acne is a common skin condition affecting people at some point duringtheir lives. Severe acne is inflammatory and often caused by infectiondue to one or more bacterial species. Oral antibiotics are a mainstay inthe treatment of acne. Minocycline is among one such antibiotic,absorbed at different rates in different portions of thegastrointestinal tract. Conventional dosage forms containing minocyclinerequire frequent ingestion of multiple doses per day, resulting in widevariations in serum concentration throughout the course of treatment andsome subjects experiencing vestibular adverse effects with immediaterelease oral dosage forms. Such downsides relating to minocycline dosageforms ultimately lead to reduced rates of subject compliance. Currentlyin the USA, SOLODYN® is available as once daily dosage form ofminocycline that provides antibiotically effective dose of approximately1 milligram per kilogram of body weight (1 mg/kg) for treating acne.

In the past, various attempts have been made to prepare modified releaseoral dosage forms of minocycline for the treatment of acne. Inparticular:

U.S. Pat. No. 4,837,030 from American Cyanamid Company relates to aminocycline dosage form that retards release in stomach and promotesrapid release in intestine. The dosage form is prepared by usingultrathin layer of a polymer particularly ethyl cellulose and hydroxypropyl methyl cellulose.

U.S. Pat. No. 5,908,838 from Medicis relates to a slowly dissolvingdosage form for oral tetracycline class antibiotics, includingminocycline, which results in the reduction of vestibular side effects.

U.S. Pat. No. 5,262,173 from American Cyanamid Company relates topulsatile once daily capsule dosage form of minocycline comprisinggranules, which are coated with pH sensitive or pH non-sensitivepolymers to provide slow release in pH about 1.0 to about 3.0 and rapidrelease in a medium having a pH about 4.5 to about 6.5, which areadministered simultaneously.

U.S. Pat. No. 5,413,777 from American Cyanamid Company relates topulsatile once daily capsule dosage form of minocycline comprisinggranules, which are coated with pH sensitive or pH non-sensitivepolymers to provide rapid release in a medium having a pH of less thanabout 3.9 and slow release in a medium having a pH from about 4.0 toabout 7.5, which are administered either simultaneously or separately upto about 120 minutes apart.

U.S. Pat. No. 5,277,916 from F. H. Faulding & Co Ltd. relates to atetracycline pharmaceutical composition comprising a plurality of coatedcore in a pellet form, which is partially soluble at an acidic pH andprovides release more slowly in the stomach than in the intestine.

U.S. Pat. No. 7,919,483 from Medicis Pharm Corp. relates to a method oftreating acne vulgaris, comprising administering a continuous slowrelease oral dosage form comprising a delivery vehicle having lactosemonohydrate, that provides 0.7 mg/kg/day to 1.3 mg/kg/day of said oralminocycline antibiotic to the subject, once daily without a loadingdose.

PCT application no. WO 2004/078111 A2 from Ranbaxy Labs Ltd. relates toextended release minocycline compositions comprising two or morehydrophilic matrix forming polymers having different viscosity.

Despite the availability of prior art dosage forms of minocycline forthe treatment of acne, there remains a need for treating acne thatprovides once daily composition for effective administration ofappropriate dose of minocycline. SOLODYN® doesn't provide flexibility ofdosing especially to subjects having swallowing disability such asdysphagia. Additionally, it contains lactose which is highly reactivedue to its hemiacetal structure and which can eventually cause chemicalinstability with active components. Further, due to the solubility ofminocycline of around 50 mg/ml, the drug has extremely poor bindingaffinity towards pharmaceutically acceptable excipients and hence, toprovide a predictable and accurate fractional dose is difficult.

Presently, in the USA, SOLODYN® or its generic versions are supplied in8 strengths—45, 55, 65, 80, 90, 105, 115 & 135 mg of minocyclinecontaining oral tablets, packaged in individual units (otherwise knownas “Stock keeping Unit” or “SKU”). These different units (havingdifferent strengths) are supplied to cater the need of subjects withbody weight from 45 kg to 135 kg. However, handling these many units(SKU) is cumbersome in manufacturing, supply chain, inventory and forchemists. Further, it would be advantageous to have reduced number of“Stock Keeping Units (SKUs)”, in order to improve the inventory inpharmacy, warehouse—drug storage or in supply chain.

SUMMARY OF THE INVENTION

Accordingly, the present application relates to a method of orallyadministering a once daily tablet of minocycline to a subject. Thetablet is substantially free of reactive excipients like lactose or itspharmaceutically acceptable hydrates, hemihydrates or anhydrous forms,and can be administered to subjects having lactose intolerance.Additionally, the tablet can be administered by dispersion into food,which provides subject compliance especially to those suffering fromdysphagia.

The present application also relates to a tablet of minocycline or apharmaceutically acceptable salt thereof, which is free of lactose orsubstantially free of lactose. The present tablets of minocycline alsocomprises one or more score(s) or separation mark(s) for dividing thetablet into equal subunits and provides efficient processes forpreparation thereof, wherein a supply of said tablet reduces SKUs by atleast 50%.

In an embodiment, the present application relates to a pharmaceuticalcomposition of minocycline.

In another embodiment, the present application relates to apharmaceutical composition of minocycline, comprising minocycline andone or more pharmaceutically acceptable excipient(s), wherein saidcomposition comprises (i) an immediate release (IR) portion and (ii) anextended release (ER) portion.

In yet another embodiment, the present application relates to apharmaceutical composition of minocycline, comprising minocycline andone or more pharmaceutically acceptable excipient(s), wherein saidcomposition comprises (i) about 20 to about 40 percent of minocycline inan immediate release (IR) portion and (ii) about 80 to about 60 percentof minocycline in an extended release (ER) portion.

In an embodiment, the present application relates to a once daily tabletof minocycline, wherein said tablet is substantially free of lactose.

In another embodiment, the present application relates to a once dailytablet of minocycline, comprising minocycline and one or morepharmaceutically acceptable excipient(s), wherein said tablet comprises(i) an immediate release (IR) portion and (ii) an extended release (ER)portion.

In yet another embodiment, the present application relates to a oncedaily tablet of minocycline, comprising minocycline and one or morepharmaceutically acceptable excipient(s), wherein said tablet comprises(i) about 20 to about 40 percent of minocycline in an immediate release(IR) portion and (ii) about 80 to about 60 percent of minocycline in anextended release (ER) portion.

In an aspect of the above embodiments, the tablet of the presentapplication comprises an immediate release (IR) portion and an extendedrelease (ER) portion present in a ratio of about 20:80 to about 40:60.

In an aspect of the above embodiments, the tablet of the presentapplication comprises one or more cushioning agent(s) that providescushion effect during the compression and fills the void space toprevent adhesion and fusion of coated release portions duringcompression.

The amount of one or more cushioning agents that may be used in thepresent application ranges from about 40% to about 60% by weight of thepresent tablets.

In one embodiment, the composition of the present application exhibitsat least one of the following dissolution profiles when measured in USPtype I apparatus at 100 rpm in 900 ml of simulated gastric fluid with apH of 2.1 and at 37° C.: about 15% to about 25% of minocycline in 15minutes, about 35% to about 50% of minocycline in 30 minutes, about 50%to about 65% of minocycline in 60 minutes, and about 70% to about 90% ofminocycline in 120 minutes.

In yet another aspect of the above embodiments, the tablet of thepresent application comprises at least one score or other means ofseparation mark(s) for dividing the tablet into two or more equalsubunits to provide a predictable and accurate fractional dose ofminocycline, wherein said divided subunits have uniformity of drugcontent.

In an aspect of the above embodiments, the tablet of the presentapplication is administered as intact or by dividing into two or moreequal subunits to provide a predictable and accurate fractional dose ofminocycline.

In an embodiment, the present application relates to a once daily oraltablet of minocycline comprising 90 mg, 105 mg, 115 mg, 135 mg or 165 mgof minocycline, wherein said tablet comprises (i) an immediate release(IR) portion, (ii) an extended release (ER) portion, and (iii) one ormore pharmaceutically acceptable excipients, and said tablet issubstantially free of lactose.

In another embodiment, the present application relates to a method oftreating acne in a subject comprising orally administering a once dailytablet of minocycline, wherein said tablet is substantially free oflactose.

In an aspect of the above embodiments, the tablet of the presentapplication comprises (i) about 20 to about 40 percent of minocycline inan immediate release (IR) portion, (ii) about 80 to about 60 percent ofminocycline in an extended release (ER) portion, and (iii) one or morepharmaceutically acceptable excipients.

In an embodiment, the present application relates to a method of orallyadministering once daily tablet of minocycline comprising 90 mg, 105 mg,115 mg, 135 mg or 165 mg of minocycline, wherein said tablet comprises(i) about 20 to about 40 percent of minocycline in an immediate release(IR) portion, (ii) about 80 to about 60 percent of minocycline in anextended release (ER) portion, and (iii) one or more pharmaceuticallyacceptable excipients, and said tablet is substantially free of lactose.

In an aspect of the above embodiments, the immediate release (IR)portion comprises about 18 mg to about 66 mg of minocycline.

In an aspect of the above embodiments, the extended release (ER) portioncomprises about 54 mg to about 132 mg of minocycline.

In an aspect of the above embodiments, the tablet of the presentapplication has at least one score or other means of separation mark(s)for dividing the tablet into two or more equal subunits to provide apredictable and accurate fractional dose of minocycline, wherein saiddivided subunits have uniformity of drug content and provide a dose ofabout 0.5-1.5 mg/kg/day or about 0.7-1.3 mg/kg/day or about 1 mg/kg/day.

In another aspect of the above embodiments, the tablet comprising 90 mgof minocycline is dispensed as intact to subjects having body weight of81-96 kg or divided into two equal subunits, wherein each subunitprovides 45 mg strengths of minocycline and dispensed to subjects havingbody weight of 40-49 kg.

In another aspect of the above embodiments, the tablet comprising 105 mgof minocycline is dispensed as intact to subjects having body weight of85-110 kg, divided into two equal subunits of 52.5 mg strengths ofminocycline and dispensed to subjects having body weight of 45-59 kg, ordivided into three equal subunits of 35 mg strengths of minocycline anddispensed to subjects having body weight of 35-39 kg.

In another aspect of the above embodiments, the tablet comprising 135 mgof minocycline dispensed as intact to subjects having body weight of111-136 kg, divided into two equal subunits of 67.5 mg strengths ofminocycline and dispensed to subjects having body weight of 60-84 kg, ordivided into three equal subunits of 45 mg strengths of minocycline anddispensed to subjects having body weight of 40-49 kg.

In another aspect of the above embodiments, the tablet comprising 165 mgof minocycline dispensed as intact to subjects having body weight of146-165 kg, divided into two equal subunits of 82.5 mg strengths ofminocycline and dispensed to subjects having body weight of 80-88 kg, ordivided into three equal subunits of 55 mg strength of minocycline anddispensed to subjects having body weight of 50-59 kg.

In an embodiment, the present application relates to an once daily oraltablet of minocycline, comprising 35 mg, 45 mg, 52.5 mg, 55 mg, 57.5 mg,67.5 mg, 70 mg, 82.5 mg, 90 mg, 105 mg, 110 mg, 115 mg, 135 mg or 165 mgof minocycline, wherein said tablet comprises (i) an immediate release(IR) portion and (ii) an extended release (ER) portion, said tablet issubstantially free of lactose, and said tablet exhibits at least one ofthe following dissolution profile when measured in USP type I apparatusat 100 rpm in 900 ml of simulated gastric fluid with a pH of 2.1 and at37° C.: about 15% to about 25% of minocycline in 15 minutes, about 35%to about 50% of minocycline in 30 minutes, about 50% to about 65% ofminocycline in 60 minutes, and about 70% to about 90% of minocycline in120 minutes.

In one embodiment, the composition of the present application exhibitsat least one of the following dissolution profile when measured in USPtype I apparatus at 100 rpm in 900 ml of acetate buffer with a pH of 4.5and at 37° C.: about 15% to about 25% of minocycline in 15 minutes,about 35% to about 45% of minocycline in 30 minutes, about 50% to about65% of minocycline in 60 minutes, and about 70% to about 90% ofminocycline in 120 minutes

In one embodiment, the composition of the present application exhibitsat least one of the following dissolution profile when measured in USPtype I apparatus at 100 rpm in 900 ml of phosphate buffer with a pH of5.5 and at 37° C.: about 15% to about 25% of minocycline in 15 minutes,about 35% to about 45% of minocycline in 30 minutes, about 50% to about65% of minocycline in 60 minutes, and about 70% to about 90% ofminocycline in 120 minutes

In another embodiment, the present application relates to an once dailyoral tablet of minocycline, comprising 90 mg, 105 mg, 115 mg, 135 mg or165 mg of minocycline, wherein said tablet is substantially free oflactose, said tablet exhibits bioequivalence to a corresponding SOLODYN®tablet when administered to healthy human subjects in fasting and fedconditions, and said bioequivalence is established by: (a) a 90%Confidence Interval for mean C_(max), which is between 80% and 125%, (b)a 90% Confidence Interval for mean AUC_((0-t)), which is between 80% and125%, and (c) a 90% Confidence Interval for mean AUC_((0-∞)), which isbetween 80% and 125%.

In another embodiment, the present application relates to a once dailyoral tablet of minocycline comprising 90 mg, 105 mg, 115 mg, 135 mg, or165 mg of minocycline, wherein said tablet comprises at least one scoreor other means of separation mark(s) for dividing the tablet into two ormore equal subunits, to provide at least 50% reduced stock keeping unitsin a pharmacy or warehouse.

In an aspect of the above embodiment, the tablet of the presentapplication is dispensed as intact or by dividing into two or more equalsubunits to provide a minocycline dose of approximately 1 mg/kg bodyweight to a subject for treating acne.

In an aspect of the above embodiments, the tablet of the presentapplication comprising 90 mg, 105 mg, 115 mg, 135 mg or 165 mg ofminocycline provides inventory optimization to a pharmacy or a warehousefor said strengths of minocycline.

In an aspect of the above embodiments, the tablet of the presentapplication comprising 90 mg of minocycline provides inventoryoptimization to a pharmacy or a warehouse by providing 45 mg or 90 mgstrengths of minocycline in scored tablets.

In an aspect of the above embodiments, the tablet of the presentapplication comprising 105 mg of minocycline provides inventoryoptimization to a pharmacy or a warehouse by providing 35 mg, 52.5 mg or105 mg strengths of minocycline in scored tablets.

In an aspect of the above embodiments, the tablet of the presentapplication comprising 135 mg of minocycline provides inventoryoptimization to a pharmacy or a warehouse by providing 45 mg, 67.5 mg or135 mg strengths of minocycline in scored tablets.

In an aspect of the above embodiments, the tablet of the presentapplication comprising 165 mg of minocycline provides inventoryoptimization to a pharmacy or a warehouse by providing 55 mg, 82.5 mg or165 mg strengths of minocycline in scored tablets.

In an aspect of the above embodiments, the minocycline is minocyclinehydrochloride.

In one aspect, the compositions of the present application aresubstantially free of lactose.

In one aspect, the compositions of the present application areadministered for the treatment of acne.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows in-vitro release profile for example 2 and SOLODYN® in 900ml of pH 2.1 Simulated Gastric Fluid, USP Type 1 apparatus at a speed of100 rpm.

FIG. 2 shows in-vitro release profile for example 2 and SOLODYN® in 900ml of pH 4.5, USP Type 1 apparatus at a speed of 100 rpm.

FIG. 3 shows in-vitro release profile for example 2 and SOLODYN® in 900ml of pH 5.5, USP Type 1 apparatus at a speed of 100 rpm.

FIG. 4A shows 72 hour plasma minocycline concentration vs. time profileof example 2 equivalent to 135 mg of minocycline and SOLODYN® (80 mg+55mg) administered to 77 healthy human subjects in fasting conditions.

FIG. 4B shows 72 hour plasma minocycline concentration vs. time profileof example 2 equivalent to 135 mg of minocycline and SOLODYN® (80 mg+55mg) administered to 77 healthy human subjects in fed conditions.

DETAILED DESCRIPTION OF THE INVENTION

The details of one or more embodiments of the present invention are setforth in this document. Modifications to embodiments described in thisdocument, and other embodiments, will be evident to those of ordinaryskill in the art after a study of the information provided in thisdocument. The information provided in this document, and particularlythe specific details of the described exemplary embodiments, is providedprimarily for clearness of understanding and no unnecessary limitationsare to be understood therefrom. In case of conflict, the specificationof this document, including definitions, will control.

Definitions

The terms as used herein have the following meanings:

The present invention can comprise or consist essentially of thecomponents of the present invention as well as other ingredients orelements described herein. As used herein, “comprising” means theelements recited, or their equivalent in structure or function, plus anyother element or elements which are not recited. The terms “having,”“including,” and “comprised of” are also to be construed as open endedunless the context suggests otherwise. As used herein, “consistingessentially of” means that the invention may include ingredients inaddition to those recited in the claim, but only if the additionalingredients do not materially alter the basic and novel characteristicsof the claimed invention.

The terms “a” and “the” as used herein, are understood to encompass theplural as well as the singular or otherwise clearly mentioned whereverneeded. For example, reference to “an excipient” includes reference toone or more of such excipients, and reference to “the vehicle” includesreference to one or more of such vehicles.

The terms “about,” “up to,” “generally,” and the like are to beconstrued as modifying a term or value such that it is not an absolute.Such terms will be defined by the circumstances and the terms that theymodify as those terms are understood by those of skill in the art. Thisincludes, at very least, the degree of expected experimental error,technical error and instrumental error for a given experiment, techniqueor an instrument used to measure a value. The term “about” is used toprovide flexibility to a numerical range endpoint by providing that agiven value may be “a little above” or “a little below” the endpoint. Asan illustration, a numerical range of “about 1 to about 5” should beinterpreted to include not only the explicitly recited values of about 1to about 5, but also include individual values and sub-ranges within theindicated range. Thus, included in this numerical range are individualvalues such as 2, 3, and 4 and sub-ranges such as from 1-3, from 2-4,and from 3-5, etc., as well as 1, 2, 3, 4, and 5, individually. Thissame principle applies to ranges reciting only one numerical value as aminimum or a maximum.

The terms “composition” and “formulation” refer to a mixture of two ormore compounds, elements, or molecules. Also this term may be used torefer to a mixture of one or more active agents with a pharmaceuticallyacceptable vehicle or excipients. Furthermore, the term “dosage form”can include one or more formulation(s) or composition(s) provided in aformat for administration like tablets, capsules, pills, minitablets,pellets, granules, powder and the like or mixtures thereof.

The term “substantially free of lactose” as used herein, refers to apharmaceutical composition of present application that has less thanabout 5%, 3%, 2%, 1%, or 0.5% w/w of lactose or pharmaceuticallyacceptable hydrates, hemihydrates, or anhydrous forms thereof by weightof the present pharmaceutical composition, while formulating or instorage of the composition.

The term “SOLODYN®” is used to represent extended release oral tabletsof minocycline or its pharmaceutical equivalents or its therapeuticequivalents or later approved drugs which are designated as AB rated byUS FDA as per Approved Drug Products with Therapeutic EquivalenceEvaluations (34^(th) edition) or drugs obtained marketing approval by USFDA through Abbreviated New Drug Application (ANDA) filing byestablishing bioequivalence to such Product. For example, in someembodiments, SOLODYN® includes minocycline hydrochloride along withexcipients such as lactose monohydrate NF, hypromellose type 2910 USP,magnesium stearate NF, colloidal silicon dioxide NF, and carnauba waxNF. In some embodiments SOLODYN® includes its US FDA approvedtherapeutic or pharmaceutical equivalents. SOLODYN® is a Trademarkregistered and owned by Medicis Pharmaceutical Corporation Delaware 7720North Dobson Road Scottdale Ariz. 85256.

The term “minocycline” as used herein, is intended to include, but notlimited to, minocycline and pharmaceutically acceptable,pharmacologically active derivatives of minocycline, including bothindividual enantiomers of minocycline (dextrogyral and levogyralenantiomers) in their substantially pure form and their pharmaceuticallyacceptable salts, mixtures (in any ratio) of minocycline enantiomers andtheir pharmaceutically acceptable salts, and active metabolites ofminocycline and their pharmaceutically acceptable salts. The chemicalformulation of minocycline is[4S-(4α,4aα,5aα,12aα)]-4,7-Bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide.The solid state form of minocycline used in the composition is notcritical. For example, minocycline can be amorphous or crystalline.

The term “pharmaceutically acceptable salts” as used herein, includesthose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like,which are well known in the art. The salts can be prepared in situduring the final isolation and purification of the compounds of theinvention, or separately by reacting the pharmaceutically activesubstance having a free base function with a suitable organic acid orinorganic acid. Examples of pharmaceutically acceptable salts include,but are not limited to, any of the salts or co-crystals of minocyclineselected from hydrochloride, hydrobromide, sulphate, citrate, phosphate,maleate, formate, acetate, nitrate, mesylate, succinate, benzoate andthe like. The salts may be in the form of solvate, hydrate,hemihydrates, or anhydrous forms.

The term “dose” as used herein, means a prescribed amount of minocyclinewhich is sufficient for the treatment of acne, but low enough to avoidserious side effects (at a reasonable benefit/risk ratio), within thescope of sound medical judgment. The effective amount of the minocyclinewill vary with the particular condition being treated, the age andphysical condition of the subject being treated, the severity of thecondition, the duration of the treatment, the nature of concurrenttherapy, and like factors within the knowledge and expertise of theattending physician.

The term “extended release” as used herein, refers to composition ordosage form of minocycline which is formulated to provide a longerduration of pharmacological response after administration of the dosageform than is ordinarily experienced after administration of acorresponding immediate release composition. Extended releasecompositions include, inter alia, those compositions described elsewhereas “controlled release”, “modified release”, “delayed release”,“sustained release”, “prolonged release”, “programmed release”, “slowrelease” “time release” and/or “rate controlled” compositions or dosageforms.

The term, “acne” as used herein, refers to various skin conditionscharacterized by papules, pustules, cysts, nodules, comedones, and otherblemishes or skin lesions. For the purposes of this specification, acnemeans all known types of acne comprising superficial acne, low gradeacne, pre-acne or acne lesions which includes, but are not limited to,acne vulgaris, cystic acne, acne atrophica, bromide acne, chlorine acne,acne conglobata, acne cosmetica, acne detergicans, epidemic acne, acneestivalis, acne fulminans, halogen acne, acne indurata, iodide acne,acne keloid, acne mechanica, acne papulosa, pomade acne, premenstralacne, acne pustulosa, acne scorbutica, acne scrofulosorum, acneurticata, acne varioliformis, acne venenata, propionic acne, acneexcoriee, gram negative acne, steroid acne, nodulocystic acne and acnerosacea.

The term, “dysphagia” as used herein, refers to collective term whichincludes swallowing problems such as difficulty in swallowing, inabilityto swallow or discomfort in swallowing or related difficulties.

The term “food dispersion” covers an edible food product in the form ofaqueous dispersion having semi-solid consistency, selected from thegroup comprising of applesauce, puree, jam, food syrups and the like ormixtures thereof.

The term “stable” as used herein, refers to chemical and physicalstability of the present tablets of minocycline when stored at 25° C.and 60% Relative Humidity (RH) for at least 12 months or at 40° C. and75% Relative Humidity (RH) for 6 months or when allowed to disperse infood dispersion for at least one hour.

The term “subject” as used herein refers to a human individual sufferingfrom acne, who is to be a recipient of the present pharmaceuticalcomposition of minocycline.

As used herein, the terms “optional” or “optionally” mean that thesubsequently described event or circumstance does or does not occur orexist and that the description includes instances where said event orcircumstance occurs or exists, and instances where it does not.

As used herein, the terms “treatment” or “treating” relate to curing orsubstantially curing a condition, as well as ameliorating at least onesymptom of the condition, and are inclusive of prophylactic treatmentand therapeutic treatment. As would be recognized by one or ordinaryskill in the art, treatment that is administered prior to clinicalmanifestation of a condition then the treatment is prophylactic (i.e.,it protects the subject against developing the condition). If thetreatment is administered after manifestation of the condition, thetreatment is therapeutic (i.e., it is intended to diminish, ameliorate,control, or maintain the existing condition and/or side effectsassociated with the condition). The terms relate to medical managementof a subject with the intent to substantially cure, ameliorate,stabilize, or substantially prevent a condition, including but notlimited to prophylactic treatment to preclude, avert, obviate,forestall, stop, or hinder something from happening, or reduce theseverity of something happening, especially by advance action. As such,the terms treatment or treating include, but are not limited to:inhibiting the progression of a condition of interest; arresting orpreventing the development of a condition of interest; reducing theseverity of a condition of interest; ameliorating or relieving symptomsassociated with a condition of interest; causing a regression of thecondition of interest or one or more of the symptoms associated with thecondition of interest; and preventing a condition of interest or thedevelopment of a condition of interest.

In an embodiment, the present application relates to a pharmaceuticalcomposition of minocycline.

In an embodiment, the present application relates to a method of orallyadministering pharmaceutical composition of minocycline to a subject inneed thereof.

In another embodiment, the present application relates to apharmaceutical composition of minocycline, comprising minocycline andone or more pharmaceutically acceptable excipient(s), wherein saidcomposition comprises (i) an immediate release (IR) portion and (ii) anextended release (ER) portion.

In yet another embodiment, the present application relates to apharmaceutical composition of minocycline, comprising minocycline andone or more pharmaceutically acceptable excipient(s), wherein saidcomposition comprises (i) about 20 to about 40 percent of minocycline inan immediate release (IR) portion and (ii) about 80 to about 60 percentof minocycline in an extended release (ER) portion.

In an aspect of the above embodiments, the IR and ER portions arepresent in a ratio of about 20:80 to about 40:60.

In an embodiment, the present application relates to a pharmaceuticalcomposition of minocycline, comprising minocycline and one or morepharmaceutically acceptable excipient(s), wherein said compositioncomprises (i) an immediate release (IR) portion and (ii) an extendedrelease (ER) portion, present in a ratio of about 20:80 to about 40:60.

In yet another embodiment, the present application relates to apharmaceutical composition of minocycline, comprising minocycline andone or more pharmaceutically acceptable excipient(s), wherein saidcomposition comprises (i) about 20 to about 40 percent of minocycline inan immediate release (IR) portion and (ii) about 80 to about 60 percentof minocycline in an extended release (ER) portion, present in a ratioof about 20:80 to about 40:60.

In an aspect of the above embodiments, the present pharmaceuticalcomposition of minocycline includes, but are not limited to, tablets,capsules, pills, minitablets, pellets, granules, powder and the like ormixtures thereof

In an embodiment, the compositions of the present application aresubstantially free of lactose.

In an embodiment, the present application relates to a method of orallyadministering once daily tablet of minocycline to a subject in needthereof.

In another embodiment, the present application relates to a once dailytablet of minocycline, comprising minocycline and one or morepharmaceutically acceptable excipient(s), wherein said tablet comprises(i) an immediate release (IR) portion and (ii) an extended release (ER)portion.

In yet another embodiment, the present application relates to a methodof orally administering once daily tablet of minocycline, to a subjectin need thereof, comprising minocycline and one or more pharmaceuticallyacceptable excipient(s), wherein said tablet comprises (i) an immediaterelease (IR) portion and (ii) an extended release (ER) portion.

In yet another embodiment, the present application relates to a oncedaily tablet of minocycline, comprising minocycline and one or morepharmaceutically acceptable excipient(s), wherein said tablet comprises(i) about 20 to about 40 percent of minocycline in an immediate release(IR) portion and (ii) about 80 to about 60 percent of minocycline in anextended release (ER) portion.

In yet another embodiment, the present application relates to a methodof orally administering once daily tablet of minocycline to a subject inneed thereof, comprising minocycline and one or more pharmaceuticallyacceptable excipient(s), wherein said tablet comprises (i) about 20 toabout 40 percent of minocycline in an immediate release (IR) portion and(ii) about 80 to about 60 percent of minocycline in an extended release(ER) portion.

In another aspect of the above embodiments, the IR and ER portions arepresent in a ratio of about 20:80 to about 40:60.

In an embodiment, the present application relates to a once daily tabletof minocycline, comprising minocycline and one or more pharmaceuticallyacceptable excipient(s), wherein said tablet comprises (i) an immediaterelease (IR) portion and (ii) an extended release (ER) portion, presentin a ratio of about 20:80 to about 40:60.

In another embodiment, the present application relates to a method oforally administering once daily tablet of minocycline to a subject inneed thereof, comprising minocycline and one or more pharmaceuticallyacceptable excipient(s), wherein said tablet comprises (i) an immediaterelease (IR) portion and (ii) an extended release (ER) portion, presentin a ratio of about 20:80 to about 40:60.

In yet another embodiment, the present application relates to a oncedaily tablet of minocycline, comprising minocycline and one or morepharmaceutically acceptable excipient(s), wherein said tablet comprises(i) about 20 to about 40 percent of minocycline in an immediate release(IR) portion and (ii) about 80 to about 60 percent of minocycline in anextended release (ER) portion, present in a ratio of about 20:80 toabout 40:60.

In yet another embodiment, the present application relates to a methodof orally administering once daily tablet of minocycline to a subject inneed thereof, comprising minocycline and one or more pharmaceuticallyacceptable excipient(s), wherein said tablet comprises (i) about 20 toabout 40 percent of minocycline in an immediate release (IR) portion and(ii) about 80 to about 60 percent of minocycline in an extended release(ER) portion, present in a ratio of about 20:80 to about 40:60.

In another embodiment, the tablet used in the method of administrationis substantially free of lactose.

In an embodiment, the present application relates to a method oftreating acne administering a pharmaceutical composition of minocycline.

In another embodiment, the present application relates to a method oftreating acne administering a pharmaceutical composition of minocycline,comprising minocycline and one or more pharmaceutically acceptableexcipient(s), wherein said composition comprises (i) an immediaterelease (IR) portion and (ii) an extended release (ER) portion.

In yet another embodiment, the present application relates to a methodof treating acne administering a pharmaceutical composition ofminocycline, comprising minocycline and one or more pharmaceuticallyacceptable excipient(s), wherein said composition comprises (i) about 20to about 40 percent of minocycline in an immediate release (IR) portionand (ii) about 80 to about 60 percent of minocycline in an extendedrelease (ER) portion.

In an aspect of the above embodiments, the IR and ER portions arepresent in a ratio of about 20:80 to about 40:60.

In an embodiment, the present application relates to a method oftreating acne administering a pharmaceutical composition of minocycline,comprising minocycline and one or more pharmaceutically acceptableexcipient(s), wherein said composition comprises (i) an immediaterelease (IR) portion and (ii) an extended release (ER) portion, presentin a ratio of about 20:80 to about 40:60.

In yet another embodiment, the present application relates to a methodof treating acne administering a pharmaceutical composition ofminocycline, comprising minocycline and one or more pharmaceuticallyacceptable excipient(s), wherein said composition comprises (i) about 20to about 40 percent of minocycline in an immediate release (IR) portionand (ii) about 80 to about 60 percent of minocycline in an extendedrelease (ER) portion, present in a ratio of about 20:80 to about 40:60.

In an aspect of the above embodiments, the present pharmaceuticalcomposition of minocycline includes, but are not limited to, tablets,capsules, pills, minitablets, pellets, granules, powder and the like ormixtures thereof

In an embodiment, the compositions of the present application aresubstantially free of lactose.

In an aspect of the above embodiments, the immediate release (IR) and/orextended release (ER) portions are present in the form of a granule,pellet, bead, spherule, powder and the like or mixtures thereof.

In an aspect of the above embodiments, a once daily tablet ofminocycline of the present application comprises one or more cushioningagent(s) that provides cushion effect during the compression and fillsthe void space to prevent adhesion and fusion of coated release portionsduring compression.

Suitable examples of one or more such cushioning agents used in thepresent application, which include, but are not limited to,microcrystalline cellulose, silicified microcrystalline cellulose,calcium phosphate, mannitol, sorbitol, polyethylene glycol, sodiumstearyl fumarate, magnesium stearate, starch, talc and the like ormixtures thereof.

The amount of one or more cushioning agents that may be used in thepresent application ranges from about 40% to about 60% by weight of thepresent tablets.

In yet another aspect of the above embodiments, a once daily tablet ofminocycline of the present application comprises immediate release (IR)and extended release (ER) portions, and one or more cushioning agent(s),wherein said release portions are present with said cushioning agent(s)in a ratio of from about 40:60 to about 50:50.

In an embodiment, the present application relates to a once daily tabletof minocycline comprising minocycline and one or more cushioningagent(s), wherein said tablet comprises (i) an immediate release (IR)portion and (ii) an extended release (ER) portion, and wherein saidrelease portions are present with said cushioning agent(s) in a ratio offrom about 40:60 to about 50:50.

In one embodiment, the present application relates to a method of orallyadministering once daily tablet of minocycline to a subject in needthereof, comprising minocycline and one or more cushioning agent(s),wherein said tablet comprises (i) an immediate release (IR) portion and(ii) an extended release (ER) portion, and wherein said release portionsare present with said cushioning agent(s) in a ratio of from about 40:60to about 50:50.

In another embodiment, the present application relates to a once dailytablet of minocycline comprising minocycline and one or more cushioningagent(s), wherein said tablet comprises (i) about 20 to about 40 percentof minocycline in an immediate release (IR) portion and (ii) about 80 toabout 60 percent of minocycline in an extended release (ER) portion, andwherein said release portions are present with said cushioning agent(s)in a ratio of from about 40:60 to about 50:50.

In another embodiment, the present application relates to a method oforally administering once daily tablet of minocycline to a subject inneed thereof, comprising minocycline and one or more cushioningagent(s), wherein said tablet comprises (i) about 20 to about 40 percentof minocycline in an immediate release (IR) portion and (ii) about 80 toabout 60 percent of minocycline in an extended release (ER) portion, andwherein said release portions are present with said cushioning agent(s)in a ratio of from about 40:60 to about 50:50.

In an embodiment, the present application relates to a once daily oraltablet of minocycline, comprising minocycline and one or morepharmaceutically acceptable excipient(s), comprising (i) an immediaterelease (IR) portion and (ii) an extended release (ER) portion and saidtablet exhibits at least one of the following dissolution profile whenmeasured in USP type I apparatus at 100 rpm in 900 ml of simulatedgastric fluid with a pH of 2.1 and at 37° C.: about 15% to about 25% ofminocycline in 15 minutes, about 35% to about 50% of minocycline in 30minutes, about 50% to about 65% of minocycline in 60 minutes, and about70% to about 90% of minocycline in 120 minutes.

In another embodiment, the present application relates to a once dailyoral tablet of minocycline, comprising minocycline and one or morepharmaceutically acceptable excipient(s), comprising (i) about 20 toabout 40 percent of minocycline in an immediate release (IR) portion and(ii) about 80 to about 60 percent of minocycline in an extended release(ER) portion and said tablet exhibits at least one of the followingdissolution profile when measured in USP type I apparatus at 100 rpm in900 ml of simulated gastric fluid with a pH of 2.1 and at 37° C.: about15% to about 25% of minocycline in 15 minutes, about 35% to about 50% ofminocycline in 30 minutes, about 50% to about 65% of minocycline in 60minutes, and about 70% to about 90% of minocycline in 120 minutes.

In an embodiment, the present application relates to a once daily oraltablet of minocycline, comprising minocycline and one or morepharmaceutically acceptable excipient(s), comprising (i) an immediaterelease (IR) portion and (ii) an extended release (ER) portion and saidtablet exhibits at least one of the following dissolution profile whenmeasured in USP type I apparatus at 100 rpm in 900 ml of acetate bufferwith a pH of 4.5 and at 37° C.: about 15% to about 25% of minocycline in15 minutes, about 35% to about 45% of minocycline in 30 minutes, about50% to about 65% of minocycline in 60 minutes, and about 70% to about90% of minocycline in 120 minutes.

In another embodiment, the present application relates to a once dailyoral tablet of minocycline, comprising minocycline and one or morepharmaceutically acceptable excipient(s), comprising (i) about 20 toabout 40 percent of minocycline in an immediate release (IR) portion and(ii) about 80 to about 60 percent of minocycline in an extended release(ER) portion and said tablet exhibits at least one of the followingdissolution profile when measured in USP type I apparatus at 100 rpm in900 ml of acetate buffer with a pH of 4.5 and at 37° C.: about 15% toabout 25% of minocycline in 15 minutes, about 35% to about 45% ofminocycline in 30 minutes, about 50% to about 65% of minocycline in 60minutes, and about 70% to about 90% of minocycline in 120 minutes.

In an embodiment, the present application relates to a once daily oraltablet of minocycline, comprising minocycline and one or morepharmaceutically acceptable excipient(s), comprising (i) an immediaterelease (IR) portion and (ii) an extended release (ER) portion and saidtablet exhibits at least one of the following dissolution profile whenmeasured in USP type I apparatus at 100 rpm in 900 ml of phosphatebuffer with a pH of 5.5 and at 37° C.: about 15% to about 25% ofminocycline in 15 minutes, about 35% to about 45% of minocycline in 30minutes, about 50% to about 65% of minocycline in 60 minutes, and about70% to about 90% of minocycline in 120 minutes.

In another embodiment, the present application relates to a once dailyoral tablet of minocycline, comprising minocycline and one or morepharmaceutically acceptable excipient(s), comprising (i) about 20 toabout 40 percent of minocycline in an immediate release (IR) portion and(ii) about 80 to about 60 percent of minocycline in an extended release(ER) portion and said tablet exhibits at least one of the followingdissolution profile when measured in USP type I apparatus at 100 rpm in900 ml of phosphate buffer with a pH of 5.5 and at 37° C.: about 15% toabout 25% of minocycline in 15 minutes, about 35% to about 45% ofminocycline in 30 minutes, about 50% to about 65% of minocycline in 60minutes, and about 70% to about 90% of minocycline in 120 minutes.

In an embodiment, the present application relates to a method of orallyadministering once daily tablet of minocycline to a subject in needthereof, comprising minocycline and one or more pharmaceuticallyacceptable excipient(s), comprising (i) an immediate release (IR)portion and (ii) an extended release (ER) portion and said tabletexhibits at least one of the following dissolution profile when measuredin USP type I apparatus at 100 rpm in 900 ml of simulated gastric fluidwith a pH of 2.1 and at 37° C.: about 15% to about 25% of minocycline in15 minutes, about 35% to about 50% of minocycline in 30 minutes, about50% to about 65% of minocycline in 60 minutes, and about 70% to about90% of minocycline in 120 minutes.

In another embodiment, the present application relates to a method oforally administering once daily tablet of minocycline to a subject inneed thereof, comprising minocycline and one or more pharmaceuticallyacceptable excipient(s), comprising (i) about 20 to about 40 percent ofminocycline in an immediate release (IR) portion and (ii) about 80 toabout 60 percent of minocycline in an extended release (ER) portion andsaid tablet exhibits at least one of the following dissolution profilewhen measured in USP type I apparatus at 100 rpm in 900 ml of simulatedgastric fluid with a pH of 2.1 and at 37° C.: about 15% to about 25% ofminocycline in 15 minutes, about 35% to about 50% of minocycline in 30minutes, about 50% to about 65% of minocycline in 60 minutes, and about70% to about 90% of minocycline in 120 minutes.

In an embodiment, the present application relates to a method of orallyadministering once daily tablet of minocycline to a subject in needthereof, comprising minocycline and one or more pharmaceuticallyacceptable excipient(s), comprising (i) an immediate release (IR)portion and (ii) an extended release (ER) portion and said tabletexhibits at least one of the following dissolution profile when measuredin USP type I apparatus at 100 rpm in 900 ml of acetate buffer with a pHof 4.5 and at 37° C.: about 15% to about 25% of minocycline in 15minutes, about 35% to about 45% of minocycline in 30 minutes, about 50%to about 65% of minocycline in 60 minutes, and about 70% to about 90% ofminocycline in 120 minutes.

In another embodiment, the present application relates to a method oforally administering once daily tablet of minocycline to a subject inneed thereof, comprising minocycline and one or more pharmaceuticallyacceptable excipient(s), comprising (i) about 20 to about 40 percent ofminocycline in an immediate release (IR) portion and (ii) about 80 toabout 60 percent of minocycline in an extended release (ER) portion andsaid tablet exhibits at least one of the following dissolution profilewhen measured in USP type I apparatus at 100 rpm in 900 ml of acetatebuffer with a pH of 4.5 and at 37° C.: about 15% to about 25% ofminocycline in 15 minutes, about 35% to about 45% of minocycline in 30minutes, about 50% to about 65% of minocycline in 60 minutes, and about70% to about 90% of minocycline in 120 minutes.

In an embodiment, the present application relates to a method of orallyadministering once daily tablet of minocycline to a subject in needthereof, comprising minocycline and one or more pharmaceuticallyacceptable excipient(s), comprising (i) an immediate release (IR)portion and (ii) an extended release (ER) portion and said tabletexhibits at least one of the following dissolution profile when measuredin USP type I apparatus at 100 rpm in 900 ml of phosphate buffer with apH of 5.5 and at 37° C.: about 15% to about 25% of minocycline in 15minutes, about 35% to about 45% of minocycline in 30 minutes, about 50%to about 65% of minocycline in 60 minutes, and about 70% to about 90% ofminocycline in 120 minutes.

In another embodiment, the present application relates to a method oforally administering once daily tablet of minocycline to a subject inneed thereof, comprising minocycline and one or more pharmaceuticallyacceptable excipient(s), comprising (i) about 20 to about 40 percent ofminocycline in an immediate release (IR) portion and (ii) about 80 toabout 60 percent of minocycline in an extended release (ER) portion andsaid tablet exhibits at least one of the following dissolution profilewhen measured in USP type I apparatus at 100 rpm in 900 ml of phosphatebuffer with a pH of 5.5 and at 37° C.: about 15% to about 25% ofminocycline in 15 minutes, about 35% to about 45% of minocycline in 30minutes, about 50% to about 65% of minocycline in 60 minutes, and about70% to about 90% of minocycline in 120 minutes.

In an embodiment, the present application relates to a method oftreating acne by administering a once daily oral tablet of minocycline,comprising minocycline and one or more pharmaceutically acceptableexcipient(s), comprising (i) an immediate release (IR) portion and (ii)an extended release (ER) portion and said tablet exhibits at least oneof the following dissolution profile when measured in USP type Iapparatus at 100 rpm in 900 ml of simulated gastric fluid with a pH of2.1 and at 37° C.: about 15% to about 25% of minocycline in 15 minutes,about 35% to about 50% of minocycline in 30 minutes, about 50% to about65% of minocycline in 60 minutes, and about 70% to about 90% ofminocycline in 120 minutes.

In another embodiment, the present application relates to a method oftreating acne by administering a once daily oral tablet of minocycline,comprising minocycline and one or more pharmaceutically acceptableexcipient(s), comprising (i) about 20 to about 40 percent of minocyclinein an immediate release (IR) portion and (ii) about 80 to about 60percent of minocycline in an extended release (ER) portion and saidtablet exhibits at least one of the following dissolution profile whenmeasured in USP type I apparatus at 100 rpm in 900 ml of simulatedgastric fluid with a pH of 2.1 and at 37° C.: about 15% to about 25% ofminocycline in 15 minutes, about 35% to about 50% of minocycline in 30minutes, about 50% to about 65% of minocycline in 60 minutes, and about70% to about 90% of minocycline in 120 minutes.

In an embodiment, the present application relates to a method oftreating acne by administering a once daily oral tablet of minocycline,comprising minocycline and one or more pharmaceutically acceptableexcipient(s), comprising (i) an immediate release (IR) portion and (ii)an extended release (ER) portion and said tablet exhibits at least oneof the following dissolution profile when measured in USP type Iapparatus at 100 rpm in 900 ml of acetate buffer with a pH of 4.5 and at37° C.: about 15% to about 25% of minocycline in 15 minutes, about 35%to about 45% of minocycline in 30 minutes, about 50% to about 65% ofminocycline in 60 minutes, and about 70% to about 90% of minocycline in120 minutes.

In another embodiment, the present application relates to a method oftreating acne by administering a once daily oral tablet of minocycline,comprising minocycline and one or more pharmaceutically acceptableexcipient(s), comprising (i) about 20 to about 40 percent of minocyclinein an immediate release (IR) portion and (ii) about 80 to about 60percent of minocycline in an extended release (ER) portion and saidtablet exhibits at least one of the following dissolution profile whenmeasured in USP type I apparatus at 100 rpm in 900 ml of acetate bufferwith a pH of 4.5 and at 37° C.: about 15% to about 25% of minocycline in15 minutes, about 35% to about 45% of minocycline in 30 minutes, about50% to about 65% of minocycline in 60 minutes, and about 70% to about90% of minocycline in 120 minutes.

In an embodiment, the present application relates to a method oftreating acne by administering a once daily oral tablet of minocycline,comprising minocycline and one or more pharmaceutically acceptableexcipient(s), comprising (i) an immediate release (IR) portion and (ii)an extended release (ER) portion and said tablet exhibits at least oneof the following dissolution profile when measured in USP type Iapparatus at 100 rpm in 900 ml of phosphate buffer with a pH of 5.5 andat 37° C.: about 15% to about 25% of minocycline in 15 minutes, about35% to about 45% of minocycline in 30 minutes, about 50% to about 65% ofminocycline in 60 minutes, and about 70% to about 90% of minocycline in120 minutes.

In another embodiment, the present application relates to a method oftreating acne by administering a once daily oral tablet of minocycline,comprising minocycline and one or more pharmaceutically acceptableexcipient(s), comprising (i) about 20 to about 40 percent of minocyclinein an immediate release (IR) portion and (ii) about 80 to about 60percent of minocycline in an extended release (ER) portion and saidtablet exhibits at least one of the following dissolution profile whenmeasured in USP type I apparatus at 100 rpm in 900 ml of phosphatebuffer with a pH of 5.5 and at 37° C.: about 15% to about 25% ofminocycline in 15 minutes, about 35% to about 45% of minocycline in 30minutes, about 50% to about 65% of minocycline in 60 minutes, and about70% to about 90% of minocycline in 120 minutes.

In an embodiment, the present application relates to a method of orallyadministering once daily tablet of minocycline to a subject in needthereof, comprising minocycline and one or more cushioning agent(s) saidtablet is optionally administered to a subject having lactoseintolerance.

In an embodiment, the present application relates to a method of orallyadministering once daily tablet of minocycline to a subject in needthereof, comprising minocycline and one or more cushioning agent(s) andsaid tablet is optionally administered to a subject by dispersing infood dispersion or water.

In an aspect of the above embodiment, the subject is having dysphagiadisorder or related swallowing difficulties.

In yet another embodiment, the present application relates to a methodof orally administering once daily tablet of minocycline to a subject inneed thereof, comprising minocycline and one or more cushioning agent(s)and said tablet is administered to a subject having dysphagia disorder.

In an aspect of the above embodiment, the present tablet of minocyclineexhibits disintegration time from about 5 minutes to about 20 minutes infood dispersion.

In an aspect of the above embodiment, the present tablet of minocyclineexhibits disintegration time of about 5, 10, 11, 12, 13, 14, 15, 16, 17,18, 19 or 20 minutes in food dispersion.

In an aspect of the above embodiment, the present tablet of minocyclineexhibits disintegration time from about 20 seconds to about 60 secondsin water.

In an aspect of the above embodiment, the present tablet of minocyclineexhibits disintegration time of about 20, 25, 30, 32, 34, 36, 38, 40,42, 44, 46, 48, 50 or 60 seconds in water.

In another embodiment, the present application relates to a method oforally administering once daily tablet of minocycline to a subject inneed thereof, comprising minocycline and one or more cushioning agent(s)and said tablet is administered to a subject by dispersing in fooddispersion.

In an aspect of the above embodiments, the present tablet of minocyclineis stable in food dispersion for at least 1 hour.

In an embodiment, the present application relates to a once daily oraltablet of minocycline comprises of 90 mg, 105 mg, 115 mg, 135 mg or 165mg of minocycline and one or more pharmaceutically acceptableexcipient(s).

In another embodiment, the present application relates to a method oftreating acne in a subject comprising orally administering once dailytablet of minocycline.

In an embodiment, the present application relates to a method oftreating acne in a subject comprising orally administering once dailytablet comprising 90 mg, 105 mg, 115 mg, 135 mg or 165 mg ofminocycline.

In another embodiment, the present application relates to a once dailyoral tablet of minocycline comprising 90 mg, 105 mg, 115 mg, 135 mg or165 mg of minocycline, wherein said tablet comprises (i) an immediaterelease (IR) portion; (ii) an extended release (ER) portion; and (iii)one or more pharmaceutically acceptable excipients.

In embodiment, the present application relates to a once daily oraltablet of minocycline comprising 90 mg, 105 mg, 115 mg, 135 mg or 165 mgof minocycline, wherein said tablet comprises (i) about 20 to about 40percent of minocycline in an immediate release (IR) portion and (ii)about 80 to about 60 percent of minocycline in an extended release (ER)portion, and (iii) one or more pharmaceutically acceptable excipients.

In an aspect of the above embodiments, the immediate release (IR)portion comprises about 18 mg to about 66 mg of minocycline.

In an aspect of the above embodiments, the extended release (ER) portioncomprises about 54 mg to about 132 mg of minocycline.

In embodiment, the present application relates to a once daily oraltablet of minocycline comprising 90 mg minocycline, wherein said tabletcomprises (i) about 20 to about 40 percent of minocycline in animmediate release (IR) portion and (ii) about 80 to about 60 percent ofminocycline in an extended release (ER) portion, and (iii) one or morepharmaceutically acceptable excipients.

In another embodiment, the present application relates to a once dailyoral tablet of minocycline comprising 90 mg minocycline, wherein saidtablet comprises (i) about 18 mg to about 36 mg minocycline in animmediate release (IR) portion; (ii) about 72 mg to about 54 mgminocycline in an extended release (ER) portion; and (iii) one or morepharmaceutically acceptable excipients.

In embodiment, the present application relates to a once daily oraltablet of minocycline comprising 105 mg minocycline, wherein said tabletcomprises (i) about 20 to about 40 percent of minocycline in animmediate release (IR) portion and (ii) about 80 to about 60 percent ofminocycline in an extended release (ER) portion, and (iii) one or morepharmaceutically acceptable excipients.

In another embodiment, the present application relates to a once dailyoral tablet of minocycline comprising 105 mg minocycline, wherein saidtablet comprises (i) about 21 mg to about 42 mg minocycline in animmediate release (IR) portion; (ii) about 84 mg to about 63 mgminocycline in an extended release (ER) portion; and (iii) one or morepharmaceutically acceptable excipients.

In embodiment, the present application relates to a once daily oraltablet of minocycline comprising 135 mg minocycline, wherein said tabletcomprises (i) about 20 to about 40 percent of minocycline in animmediate release (IR) portion and (ii) about 80 to about 60 percent ofminocycline in an extended release (ER) portion, and (iii) one or morepharmaceutically acceptable excipients.

In another embodiment, the present application relates to a once dailyoral tablet of minocycline comprising 135 mg minocycline, wherein saidtablet comprises (i) about 27 mg to about 54 mg minocycline in animmediate release (IR) portion; (ii) about 108 mg to about 81 mgminocycline in an extended release (ER) portion; and (iii) one or morepharmaceutically acceptable excipients.

In embodiment, the present application relates to a once daily oraltablet of minocycline comprising 115 mg minocycline, wherein said tabletcomprises (i) about 20 to about 40 percent of minocycline in animmediate release (IR) portion and (ii) about 80 to about 60 percent ofminocycline in an extended release (ER) portion, and (iii) one or morepharmaceutically acceptable excipients.

In another embodiment, the present application relates to a once dailyoral tablet of minocycline comprising 115 mg minocycline, wherein saidtablet comprises (i) about 23 mg to about 46 mg minocycline in animmediate release (IR) portion; (ii) about 92 mg to about 69 mgminocycline in an extended release (ER) portion; and (iii) one or morepharmaceutically acceptable excipients.

In embodiment, the present application relates to a once daily oraltablet of minocycline comprising 165 mg minocycline, wherein said tabletcomprises (i) about 20 to about 40 percent of minocycline in animmediate release (IR) portion and (ii) about 80 to about 60 percent ofminocycline in an extended release (ER) portion, and (iii) one or morepharmaceutically acceptable excipients.

In another embodiment, the present application relates to a once dailyoral tablet of minocycline comprising 165 mg minocycline, wherein saidtablet comprises (i) about 33 mg to about 66 mg minocycline in animmediate release (IR) portion; (ii) about 132 mg to about 99 mgminocycline in an extended release (ER) portion; and (iii) one or morepharmaceutically acceptable excipients.

In an embodiment, the present application relates to a method of orallyadministering once daily tablet of minocycline comprising 90 mg, 105 mg,115 mg, 135 mg, or 165 mg of minocycline, wherein said tablet comprises(i) about 18 mg to about 66 mg minocycline in an immediate release (IR)portion; (ii) about 54 mg to about 132 mg minocycline in an extendedrelease (ER) portion; and (iii) one or more pharmaceutically acceptableexcipients.

In an embodiment, the present application relates to a to a method oftreating acne in a subject comprising orally administering once dailytablet of minocycline, comprising 90 mg, 105 mg, 115 mg, 135 mg, or 165mg of minocycline, wherein said tablet comprises (i) about 18 mg toabout 66 mg minocycline in an immediate release (IR) portion; (ii) about54 mg to about 132 mg minocycline in an extended release (ER) portion;and (iii) one or more pharmaceutically acceptable excipients.

In another embodiment, the present application relates to a method oforally administering once daily tablet of minocycline comprising 90 mg,105 mg, 115 mg, 135 mg, or 165 mg of minocycline, wherein said tabletcomprises (i) about 20 to about 40 percent of minocycline in animmediate release (IR) portion; (ii) about 80 to about 60 percent ofminocycline in an extended release (ER) portion; and (iii) one or morepharmaceutically acceptable excipients.

In yet another embodiment, the present application relates to a methodof treating acne in a subject comprising orally administering once dailytablet of minocycline, wherein said tablet comprises (i) about 20 toabout 40 percent of minocycline in an immediate release (IR) portion;(ii) about 80 to about 60 percent of minocycline in an extended release(ER) portion; and (iii) one or more pharmaceutically acceptableexcipients.

In yet another embodiment, the present application relates to a methodof treating acne in a subject comprising orally administering once dailytablet of minocycline, comprising 165 mg, 135 mg, 105 mg or 90 mg ofminocycline, wherein said tablet comprises (i) about 20 to about 40percent of minocycline in an immediate release (IR) portion; (ii) about80 to about 60 percent of minocycline in an extended release (ER)portion; and (iii) one or more pharmaceutically acceptable excipients.

In an aspect of the above embodiments, the immediate release (IR) andextended release (ER) portions are present in a ratio of about 20:80 toabout 40:60. In an aspect of the above embodiments, a once daily tabletof minocycline of the present application comprises one or morecushioning agent(s) selected from, but are not limited to,microcrystalline cellulose, silicified microcrystalline cellulose,calcium phosphate, mannitol, sorbitol, polyethylene glycol, sodiumstearyl fumarate, magnesium stearate, starch, talc and the like ormixtures thereof.

The amount of one or more cushioning agents that may be used in thepresent application ranges from about 40% to about 60% by weight of thepresent tablets.

In yet another aspect of the above embodiments, a once daily tablet ofminocycline of the present application comprises immediate release (IR)and extended release (ER) portions, and one or more cushioning agent(s),wherein said release portions are present with said cushioning agent(s)in a ratio of from about 40:60 to about 50:50.

In an aspect of the above embodiments, the tablet of the presentapplication comprising minocycline has at least one score or other meansof separation mark(s) for dividing the tablet into two or more equalsubunits to provide a predictable and accurate fractional dose ofminocycline, wherein said divided subunits have uniformity of drugcontent.

In an aspect of the above embodiments, the tablet of the presentapplication comprising minocycline is administered as intact or bydividing into two or more equal subunits to provide a predictable andaccurate fractional dose of minocycline.

In an aspect of the above embodiments, the tablet of the presentapplication comprising minocycline has at least one score or other meansof separation mark(s) for dividing the tablet into two or more equalsubunits to provide a predictable and accurate fractional dose ofminocycline, wherein said divided subunits have uniformity of drugcontent and provide minocycline dose of about 1 mg/kg body weight.

In an aspect of the above embodiments, the tablet of the presentapplication comprising minocycline has at least one score or other meansof separation mark(s) for dividing the tablet into two or more equalsubunits to provide a predictable and accurate fractional dose ofminocycline, wherein said divided subunits have uniformity of drugcontent and provide minocycline dose of about 0.5-1.5 mg/kg/day or about0.7-1.3 mg/kg/day or about 1 mg/kg/day.

In yet another embodiment, the present application relates to a oncedaily oral tablet of minocycline comprising 90 mg minocycline, whereinsaid tablet comprises (i) about 18 mg to about 36 mg minocycline in animmediate release (IR) portion; (ii) about 72 mg to about 54 mgminocycline in an extended release (ER) portion; and (iii) one or morepharmaceutically acceptable excipients, wherein said tablet comprises atleast one score or other means of separation mark(s) for dividing thetablet into two equal subunits to provide a predictable and accuratefractional dose.

In another embodiment, the present application relates to a once dailyoral tablet of minocycline comprising 105 mg minocycline, wherein saidtablet comprises (i) about 21 mg to about 42 mg minocycline in animmediate release (IR) portion; (ii) about 84 mg to about 63 mgminocycline in an extended release (ER) portion; and (iii) one or morepharmaceutically acceptable excipients, wherein said tablet comprises atleast one score or other means of separation mark(s) for dividing thetablet into two equal subunits to provide a predictable and accuratefractional dose.

In another embodiment, the present application relates to a once dailyoral tablet of minocycline comprising 115 mg minocycline, wherein saidtablet comprises (i) about 23 mg to about 46 mg minocycline in animmediate release (IR) portion; (ii) about 92 mg to about 66 mgminocycline in an extended release (ER) portion; and (iii) one or morepharmaceutically acceptable excipients, wherein said tablet comprises atleast one score or other means of separation mark(s) for dividing thetablet into two equal subunits to provide a predictable and accuratefractional dose.

In another embodiment, the present application relates to a once dailyoral tablet of minocycline comprising 135 mg minocycline, wherein saidtablet comprises (i) about 27 mg to about 54 mg minocycline in animmediate release (IR) portion; (ii) about 108 mg to about 81 mgminocycline in an extended release (ER) portion; and (iii) one or morepharmaceutically acceptable excipients, wherein said tablet comprises atleast one score or other means of separation mark(s) for dividing thetablet into two equal subunits to provide a predictable and accuratefractional dose.

In another embodiment, the present application relates to a once dailyoral tablet of minocycline comprising 165 mg minocycline, wherein saidtablet comprises (i) about 33 mg to about 66 mg minocycline in animmediate release (IR) portion; (ii) about 132 mg to about 99 mgminocycline in an extended release (ER) portion; and (iii) one or morepharmaceutically acceptable excipients, wherein said tablet comprises atleast one score or other means of separation mark(s) for dividing thetablet into equal subunits to provide a predictable and accuratefractional dose.

In yet another embodiment, the present application relates to a methodof orally administering once daily tablet of minocycline comprising 90mg, 105 mg, 115 mg, 135 mg, or 165 mg of minocycline, wherein saidtablet comprises (i) about 18 mg to about 66 mg minocycline in animmediate release (IR) portion; (ii) about 54 mg to about 132 mgminocycline in an extended release (ER) portion; and (iii) one or morepharmaceutically acceptable excipients, wherein said tablet comprises atleast one score or other means of separation mark(s) for dividing thetablet into two equal subunits to provide a predictable and accuratefractional dose.

In yet another embodiment, the present application relates to a methodof treating acne in a subject comprising orally administering once dailytablet of minocycline, comprising 90 mg, 105 mg, 115 mg, 135 mg or 165mg of minocycline, wherein said tablet comprises (i) about 18 mg toabout 66 mg minocycline in an immediate release (IR) portion; (ii) about54 mg to about 132 mg minocycline in an extended release (ER) portion;and (iii) one or more pharmaceutically acceptable excipients, whereinsaid tablet comprises at least one score or other means of separationmark(s) for dividing the tablet into two equal subunits to provide apredictable and accurate fractional dose.

In an embodiment, the present application relates to a method of orallyadministering once daily tablet of minocycline to a subject in needthereof, comprising 90 mg, 105 mg, 115 mg, 135 mg or 165 mg ofminocycline, wherein said tablet is administered as intact or bydividing into two or more equal subunits to provide minocycline dose ofabout 1 mg/kg body weight.

In another embodiment, the present application relates to a method oftreating acne in a subject comprising orally administering once dailytablet of minocycline, comprising 90 mg, 105 mg, 115 mg, 135 mg or 165mg of minocycline, wherein said tablet is administered as intact or bydividing into two or more equal subunits to provide minocycline dose ofabout 1 mg/kg body weight.

In an embodiment, the present application relates to a once daily oraltablet of minocycline comprising 90 mg, 105 mg, 115 mg, 135 mg or 165 mgof minocycline and one or more pharmaceutically acceptable excipient(s),wherein said tablet comprises (i) an immediate release (IR) portion;(ii) an extended release (ER) portion; and (iii) one or morepharmaceutically acceptable excipients and provides minocycline dose ofabout 1 mg/kg body weight.

In another embodiment, the present application relates to a method oforally administering once daily tablet of minocycline comprising 90 mg,105 mg, 115 mg, 135 mg or 165 mg of minocycline and one or morepharmaceutically acceptable excipient(s), wherein said tablet comprises(i) an immediate release (IR) portion; (ii) an extended release (ER)portion; and (iii) one or more pharmaceutically acceptable excipientsand provides minocycline dose of about 1 mg/kg body weight.

In yet another embodiment, the present application relates to a methodof treating acne in a subject comprising orally administering once dailytablet of minocycline, comprising 90 mg, 105 mg, 115 mg, 135 mg or 165mg of minocycline and one or more pharmaceutically acceptableexcipient(s), wherein said tablet comprises (i) an immediate release(IR) portion; (ii) an extended release (ER) portion; and (iii) one ormore pharmaceutically acceptable excipients and provides minocyclinedose of about 1 mg/kg body weight.

In an aspect of the above embodiments, the tablet of the presentapplication comprising minocycline has homogeneity of the amount ofminocycline as intact tablet and even after dividing into equalsubunits, wherein the content uniformity is about 90.0% to 105.0% of thelabel claim and the relative standard deviation is less than 2.0%, whenmeasured by content uniformity test as per United States Pharmacopoeia(USP).

In an aspect of the above embodiments, the once daily tablet comprising90 mg, 105 mg, 115 mg, 135 mg or 165 mg of minocycline of the presentapplication provides minocycline dose of approximately about 0.5-1.5mg/kg/day or about 0.7-1.3 mg/kg/day or about 1 mg/kg/day, wherein saidtablet is dispensed to a subject for treating acne, as intact or bydividing into equal subunits according to the body weight of saidsubjects, as mentioned below:

Subject's body weight Tablet strength mg/kg/day (kg) (mg) dose 35-39 35 1.0-0.89 40-49 45 1.12-0.91 45-49 52.5 1.17-1.07 50-59 52.5 1.05-0.8950-59 55  1.1-0.93 60-71 67.5 1.13-0.95 72-84 67.5 0.94-0.80 60-80 701.16-0.87 80-88 82.5 0.96-1.06 81-96 90 1.11-0.93 85-96 105 1.24-1.09 97-110 105 1.08-0.95 110-120 110  1.0-0.91 111-125 135 1.22-1.08126-136 135 1.07-0.99 146-165 165 1.13-1.0 

In an aspect of the above embodiments, the tablet of the presentapplication comprising 90 mg of minocycline upon dividing into two equalsubunits provides 45 mg strengths of minocycline.

In an aspect of the above embodiments, the tablet of the presentapplication comprising 90 mg of minocycline dispenses as intact tosubjects having body weight of 81-96 mg.

In an aspect of the above embodiments, the tablet of the presentapplication comprising 90 mg of minocycline, wherein said tablet upondividing into two equal subunits provides 45 mg strengths of minocyclineand dispensed to subjects having body weight of 40-49 kg.

In an aspect of the above embodiments, the tablet of the presentapplication comprising 105 mg of minocycline provides 35 mg, 52.5 mg or105 mg strengths of minocycline.

In an aspect of the above embodiments, the tablet of the presentapplication comprising 105 mg of minocycline upon dividing into twoequal subunits provides 52.5 mg strengths of minocycline.

In an aspect of the above embodiments, the tablet of the presentapplication comprising 105 mg of minocycline upon dividing into threeequal subunits provides 35 mg strengths of minocycline.

In an aspect of the above embodiments, the tablet of the presentapplication comprising 105 mg of minocycline dispensed as intact tosubjects having body weight of 85-110 kg.

In an aspect of the above embodiments, the tablet of the presentapplication comprising 105 mg of minocycline, wherein said tablet upondividing into two equal subunits provides 52.5 mg strengths ofminocycline and dispensed to subjects having body weight of 45-59 kg.

In an aspect of the above embodiments, the tablet of the presentapplication comprising 115 mg of minocycline, wherein said tablet upondividing into two equal subunits provides 57.5 mg strengths ofminocycline.

In an aspect of the above embodiments, the tablet of the presentapplication comprising 115 mg of minocycline provides 57.5 mg or 115 mgstrengths of minocycline.

In an aspect of the above embodiments, the tablet of the presentapplication comprising 105 mg of minocycline, wherein said tablet upondividing into three equal subunits provides 35 mg strengths ofminocycline and dispensed to subjects having body weight of 35-39 kg.

In an aspect of the above embodiments, the tablet of the presentapplication comprising 135 mg of minocycline provides 45 mg, 67.5 mg or135 mg strengths of minocycline.

In an aspect of the above embodiments, the tablet of the presentapplication comprising 135 mg of minocycline upon dividing into twoequal subunits provides 67.5 mg strengths of minocycline.

In an aspect of the above embodiments, the tablet of the presentapplication comprising 135 mg of minocycline upon dividing into threeequal subunits provides 45 mg strengths of minocycline.

In an aspect of the above embodiments, the tablet of the presentapplication comprising 135 mg of minocycline dispensed as intact tosubjects having body weight of 111-136 kg.

In an aspect of the above embodiments, the tablet of the presentapplication comprising 135 mg of minocycline, wherein said tablet upondividing into two equal subunits provides 67.5 mg strengths ofminocycline and dispensed to subjects having body weight of 60-84 kg.

In an aspect of the above embodiments, the tablet of the presentapplication comprising 135 mg of minocycline, wherein said tablet upondividing into three equal subunits provides 45 mg strengths ofminocycline and dispensed to subjects having body weight of 40-49 kg.

In an aspect of the above embodiments, the tablet of the presentapplication comprising 165 mg of minocycline provides 55 mg, 82.5 mg or165 mg strengths of minocycline.

In an aspect of the above embodiments, the tablet of the presentapplication comprising 165 mg of minocycline upon dividing into twoequal subunits provides 82.5 mg strengths of minocycline.

In an aspect of the above embodiments, the tablet of the presentapplication comprising 165 mg of minocycline upon dividing into threeequal subunits provides 55 mg strengths of minocycline.

In an aspect of the above embodiments, the tablet of the presentapplication comprising 165 mg of minocycline dispensed as intact tosubjects having body weight of 146-165 kg.

In an aspect of the above embodiments, the tablet of the presentapplication comprising 165 mg of minocycline, wherein said tablet upondividing into two equal subunits provides 82.5 mg strengths ofminocycline and dispensed to subjects having body weight of 80-88 kg.

In an aspect of the above embodiments, the tablet of the presentapplication comprising 165 mg of minocycline, wherein said tablet upondividing into three equal subunits provides 55 mg strengths ofminocycline and dispensed to subjects having body weight of 50-59 kg.

In an aspect of the above embodiments, the tablet of the presentapplication comprising 90 mg of minocycline dispensed, (i) as intact tosubjects having body weight of 81-96 kg or (ii) by dividing into twoequal subunits, wherein each subunit provides 45 mg strengths ofminocycline and dispensed to subjects having body weight of 40-49 kg.

In an aspect of the above embodiments, the tablet of the presentapplication comprising 105 mg of minocycline dispensed, (i) as intact tosubjects having body weight of 85-110 kg or (ii) by dividing into twoequal subunits, wherein each subunit provides 52.5 mg strengths ofminocycline and dispensed to subjects having body weight of 45-59 kg or(iii) by dividing into three subunits, wherein each subunit provides 35mg strengths of minocycline and dispensed to subjects having body weightof 35-39 kg.

In an aspect of the above embodiments, the tablet of the presentapplication comprising 135 mg of minocycline dispensed, (i) as intact tosubjects having body weight of 111-136 kg or (ii) by diving into twoequal subunits, wherein each subunit provides 67.5 mg strengths ofminocycline and dispensed to subjects having body weight of 60-84 kg or(iii) by diving into three subunits, wherein each subunit provides 45 mgstrengths of minocycline and dispensed to subjects having body weight of40-49 kg.

In an aspect of the above embodiments, the tablet of the presentapplication comprising 165 mg of minocycline dispensed, (i) as intact tosubjects having body weight of 146-165 kg or (ii) by dividing into twoequal subunits, wherein each subunit provides 82.5 mg strengths ofminocycline and dispensed to subjects having body weight of 80-88 kg or(iii) by dividing into three equal subunits, wherein each subunitprovides 55 mg strengths of minocycline and dispensed to subjects havingbody weight of 50-59 kg.

In an aspect of the above embodiments, the tablet of the presentapplication is administered to a subject for treating acne.

In an aspect of the above embodiments, the tablet of the presentapplication comprising minocycline is administered as intact or upondividing into two or more equal subunits, wherein said each subunits andan intact tablet exhibit the similar dissolution profiles when measuredin USP type I apparatus at 100 rpm in 900 ml of simulated gastric fluidwith a pH of 2.1 and at 37° C.

In an aspect of the above embodiments, the tablet of the presentapplication comprising minocycline is administered as intact or upondividing into two or more equal subunits, wherein said each subunits andan intact tablet exhibit at least one of the following dissolutionprofile when measured in USP type I apparatus at 100 rpm in 900 ml ofsimulated gastric fluid with a pH of 2.1 and at 37° C.: about 15% toabout 25% of minocycline in 15 minutes, about 35% to about 50% ofminocycline in 30 minutes, about 50% to about 65% of minocycline in 60minutes, and about 70% to about 90% of minocycline in 120 minutes.

In an aspect of the above embodiments, the tablet of the presentapplication comprising minocycline is administered as intact or upondividing into two or more equal subunits, wherein said each subunits andan intact tablet exhibit the similar dissolution profiles when measuredin USP type I apparatus at 100 rpm in 900 ml of acetate buffer with a pHof 4.5 and at 37° C.

In an aspect of the above embodiments, the tablet of the presentapplication comprising minocycline is administered as intact or upondividing into two or more equal subunits, wherein said each subunits andan intact tablet exhibit at least one of the following dissolutionprofiles when measured in USP type I apparatus at 100 rpm in 900 ml ofacetate buffer with a pH of 4.5 and at 37° C.: about 15% to about 25% ofminocycline in 15 minutes, about 35% to about 45% of minocycline in 30minutes, about 50% to about 65% of minocycline in 60 minutes, and about70% to about 90% of minocycline in 120 minutes.

In an aspect of the above embodiments, the tablet of the presentapplication comprising minocycline is administered as intact or upondividing into two or more equal subunits, wherein said each subunits andan intact tablet exhibit the similar dissolution profiles when measuredin USP type I apparatus at 100 rpm in 900 ml of phosphate buffer with apH of 5.5 and at 37° C.

In an aspect of the above embodiments, the tablet of the presentapplication comprising minocycline is administered as intact or upondividing into two or more equal subunits, wherein said each subunits andan intact tablet exhibit at least one of the following dissolutionprofiles when measured in USP type I apparatus at 100 rpm in 900 ml ofphosphate buffer with a pH of 5.5 and at 37° C.: about 15% to about 25%of minocycline in 15 minutes, about 35% to about 45% of minocycline in30 minutes, about 50% to about 65% of minocycline in 60 minutes, andabout 70% to about 90% of minocycline in 120 minutes.

In an embodiment, the present application relates to a composition ofminocycline, comprising minocycline and one or more pharmaceuticallyacceptable excipient(s), comprising (i) an immediate release (IR)portion and (ii) an extended release (ER) portion and said tablet whenadministered to healthy human subjects, provides T_(max) of about 1.5hours to about 3.75 hours.

In an embodiment, the present application relates to a composition ofminocycline, comprising minocycline and one or more pharmaceuticallyacceptable excipient(s), comprising (i) an immediate release (IR)portion and (ii) an extended release (ER) portion and said tablet whenadministered to healthy human subjects in fasting condition, providesT_(max) of about 1.5 hours to about 2.5 hours.

In another embodiment, the present application relates to a compositionof minocycline, comprising minocycline and one or more pharmaceuticallyacceptable excipient(s), comprising (i) an immediate release (IR)portion and (ii) an extended release (ER) portion and said tablet whenadministered to healthy human subjects in fed condition, providesT_(max) of about 2.5 hours to about 4.5 hours.

In another embodiment, the composition of the present application isprovided in various minocycline strengths such as about 10 mg to about165 mg, specifically about 10 mg to about 135 mg.

In another embodiment, various minocycline strengths of the presentapplication include, but not limited to, 10 mg, 15 mg, 20 mg, 25 mg, 30mg, 35 mg, 40 mg, 45 mg, 52.5 mg, 55 mg, 67.5 mg, 70 mg, 82.5 mg, 90 mg,1.5 mg, 110 mg, 115 mg, 135 mg and 165 mg.

In an embodiment, the present application relates to a once daily oraltablet of minocycline, comprising minocycline and one or morepharmaceutically acceptable excipient(s), comprising (i) an immediaterelease (IR) portion and (ii) an extended release (ER) portion and saidtablet when administered to healthy human subjects, provides T_(max) ofabout 1.5 hours to about 3.75 hours.

In an embodiment, the present application relates to a once daily oraltablet of minocycline, comprising minocycline and one or morepharmaceutically acceptable excipient(s), comprising (i) an immediaterelease (IR) portion and (ii) an extended release (ER) portion and saidtablet when administered to healthy human subjects in fasting condition,provides T_(max) of about 1.5 hours to about 2.5 hours.

In another embodiment, the present application relates to a once dailyoral tablet of minocycline, comprising minocycline and one or morepharmaceutically acceptable excipient(s), comprising (i) an immediaterelease (IR) portion and (ii) an extended release (ER) portion and saidtablet when administered to healthy human subjects in fed condition,provides T_(max) of about 2.5 hours to about 4.5 hours.

In an embodiment, the present application relates to a once daily oraltablet of minocycline, comprising minocycline and one or morepharmaceutically acceptable excipient(s), comprising (i) about 20 toabout 40 percent of minocycline in an immediate release (IR) portion and(ii) about 80 to about 60 percent of minocycline in an extended release(ER) portion and said tablet when administered to healthy human subjectsin fasting condition, provides T_(max) of about 1.5 hours to about 2.5hours.

In another embodiment, the present application relates to a once dailyoral tablet of minocycline, comprising minocycline and one or morepharmaceutically acceptable excipient(s), comprising (i) about 20 toabout 40 percent of minocycline in an immediate release (IR) portion and(ii) about 80 to about 60 percent of minocycline in an extended release(ER) portion and said tablet when administered to healthy human subjectsin fed condition, provides T_(max) of about 2.5 hours to about 4.5hours.

In an embodiment, the present application relates to a once daily oraltablet of minocycline, comprising 135 mg of minocycline and one or morepharmaceutically acceptable excipient(s), comprising (i) an immediaterelease (IR) portion and (ii) an extended release (ER) portion and saidtablet when administered to healthy human subjects in fasting and fedconditions, provides at least one of the following pharmacokineticparameters: (a) a C_(max) of about 400.00 ng/ml to about 1000.00 ng/ml,(b) an AUC_((0-t)) of about 7000.00 ng·hr/ml to about 15500.00 ng·hr/ml,and (c) an AUC_((0-∞)) ranging from about 7500.00 ng·hr/ml to about16500.00 ng·hr/ml.

In another embodiment, the present application relates to a once dailyoral tablet of minocycline, comprising 135 mg of minocycline and one ormore pharmaceutically acceptable excipient(s), comprising (i) about 20to about 40 percent of minocycline in an immediate release (IR) portionand (ii) about 80 to about 60 percent of minocycline in an extendedrelease (ER) portion and said tablet when administered to healthy humansubjects in fasting and fed conditions, provides at least one of thefollowing pharmacokinetic parameters: (a) a C_(max) of about 400.00ng/ml to about 1000.00 ng/ml, (b) an AUC_((0-t)) of about 7000.00ng·hr/ml to about 15500.00 ng·hr/ml, and (c) an AUC_((0-∞)) ranging fromabout 7500.00 ng·hr/ml to about 16500.00 ng·hr/ml.

In another embodiment, the present application provides a composition ofminocycline, comprising minocycline strength up to 165 mg and one ormore pharmaceutically acceptable excipient(s), comprising (i) animmediate release (IR) portion and (ii) an extended release (ER) portionand said composition is having dose-proportional pharmacokineticprofile.

In another embodiment, the present application provides a once dailyoral tablet of minocycline, comprising other minocycline dose such as 35mg, 45 mg, 52.5 mg, 55 mg, 57.5 mg, 67.5 mg, 70 mg, 82.5 mg, 90 mg, 105mg, 110 mg, 115 mg, 135 mg or 165 mg and one or more pharmaceuticallyacceptable excipient(s), comprising (i) an immediate release (IR)portion and (ii) an extended release (ER) portion and said tablet ishaving dose-proportional pharmacokinetic profile.

In another embodiment, the present application provides a composition ofminocycline, comprising minocycline strength up to 165 mg and one ormore pharmaceutically acceptable excipient(s), comprising (i) animmediate release (IR) portion and (ii) an extended release (ER) portionand said composition is having dose-proportional C_(max), AUC_((0-t))and AUC_((0-∞)) values.

In another embodiment, the present application provides a once dailyoral tablet of minocycline, comprising other minocycline dose such as 35mg, 45 mg, 52.5 mg, 55 mg, 57.5 mg, 67.5 mg, 70 mg, 82.5 mg, 90 mg, 105mg, 110 mg, 115 mg, 135 mg or 165 mg and one or more pharmaceuticallyacceptable excipient(s), comprising (i) an immediate release (IR)portion and (ii) an extended release (ER) portion and said tablet ishaving dose-proportional C_(max), AUC_((0-t)) and AUC_((0-∞)) values.

In another embodiment, the present application provides a composition ofminocycline, comprising minocycline strength up to 135 mg and one ormore pharmaceutically acceptable excipient(s), comprising (i) animmediate release (IR) portion and (ii) an extended release (ER) portionand said composition is having dose-proportional pharmacokineticprofile.

In another embodiment, the present application provides a composition ofminocycline, comprising minocycline strength up to 135 mg and one ormore pharmaceutically acceptable excipient(s), comprising (i) animmediate release (IR) portion and (ii) an extended release (ER) portionand said composition is having dose-proportional C_(max), AUC_((0-t))and AUC_((0-∞)) values.

In one embodiment, the composition of the present application isadministered to subjects in fasting and/or fed conditions.

In an aspect of the above embodiments, the tablet of the presentapplication comprising minocycline exhibits bioequivalence to acorresponding SOLODYN® tablet when administered to healthy humansubjects in fasting and fed conditions.

In an embodiment, the present application relates to a once daily oraltablet of minocycline, comprising minocycline and one or morepharmaceutically acceptable excipient(s), wherein said tablet comprises(i) an immediate release (IR) portion and (ii) an extended release (ER)portion and said tablet exhibits bioequivalence to a correspondingSOLODYN® tablet when administered to healthy human subjects in fastingand fed conditions.

In an embodiment, the present application relates to a once daily oraltablet of minocycline, comprising 35 mg, 45 mg, 52.5 mg, 55 mg, 57.5 mg,67.5 mg, 70 mg, 82.5 mg, 90 mg, 105 mg, 110 mg, 115 mg, 135 mg or 165 mgof minocycline and one or more pharmaceutically acceptable excipient(s),wherein said tablet comprises (i) an immediate release (IR) portion and(ii) an extended release (ER) portion and said tablet exhibits abioequivalence to a corresponding SOLODYN® strength when administered tohealthy human subjects.

In one aspect of the above embodiment, said tablet comprises (i) about20 to about 40 percent of minocycline in an immediate release (IR)portion and (ii) about 80 to about 60 percent of minocycline in anextended release (ER) portion.

In another embodiment, the present application relates to a once dailyoral tablet of minocycline, comprising minocycline and one or morepharmaceutically acceptable excipient(s), wherein said tablet comprises(i) about 20 to about 40 percent of minocycline in an immediate release(IR) portion and (ii) about 80 to about 60 percent of minocycline in anextended release (ER) portion and said tablet exhibits bioequivalence toa corresponding SOLODYN® tablet when administered to healthy humansubjects in fasting and fed conditions.

In an aspect of the above embodiments, the tablet of the presentapplication comprising minocycline and one or more pharmaceuticallyacceptable excipient(s) and said tablet exhibits bioequivalence to acorresponding SOLODYN® tablet when administered to healthy humansubjects in fasting and fed conditions, and said bioequivalence isestablished by: (a) a 90% Confidence Interval for mean C_(max), which isbetween 80% and 125%, (b) a 90% Confidence Interval for meanAUC_((0-t)), which is between 80% and 125% and (c) a 90% ConfidenceInterval for mean AUC_((0-∞)), which is between 80% and 125%.

In an embodiment, the present application relates to a once daily oraltablet of minocycline, comprising 35 mg, 45 mg, 52.5 mg, 55 mg, 57.5 mg,67.5 mg, 70 mg, 82.5 mg, 90 mg, 105 mg, 115 mg, 110 mg, 135 mg or 165 mgof minocycline and one or more pharmaceutically acceptable excipient(s),wherein said tablet comprises (i) an immediate release (IR) portion and(ii) an extended release (ER) portion and said tablet exhibits abioequivalence to a corresponding SOLODYN® dose when administered tohealthy human subjects, and said bioequivalence is established by: (a) a90% Confidence Interval for mean C_(max), which is between 80% and 125%,(b) a 90% Confidence Interval for mean AUC_((0-t)), which is between 80%and 125% and (c) a 90% Confidence Interval for mean AUC_((0-∞)), whichis between 80% and 125%.

In an embodiment, the present application relates to a process ofpreparing once daily oral tablet of minocycline comprising the steps of:(i) preparing an immediate release (IR) portion; (ii) preparing anextended release (ER) portion; (iii) combining the IR and ER portionswith one or more cushioning agent(s); and (iv) compressing the mixtureof (iii) into a tablet.

In another embodiment, the present application relates to a process ofpreparing once daily oral tablet of minocycline, comprising the stepsof: (i) preparing an immediate release (IR) portion comprising about 20to about 40 percent of minocycline; (ii) preparing an extended release(ER) portion comprising about 80 to about 60 percent of minocycline;(iii) combining the IR and ER portions with one or more one or morecushioning agent(s); and (iv) compressing the mixture of (iii) into atablet.

In another embodiment, the present application relates to a process ofpreparing once daily oral tablet of minocycline, comprising the stepsof: (i) preparing an immediate release (IR) portion comprising about 18mg to about 66 mg of minocycline; (ii) preparing an extended release(ER) portion comprising about 54 mg to about 132 mg of minocycline;(iii) combining the IR and ER portions with one or more one or morecushioning agent(s); and (iv) compressing the mixture of (iii) into atablet.

In an aspect of the above embodiments, the process involves coating orlayering of minocycline over inert cores with coating or layeringmaterials comprising minocycline solution and other suitablepharmaceutical excipients like binders, plasticizers or disintegrantsover the inert cores.

The process of coating or layering includes any method known to a personskilled in the art such as, but not limited to, by spraying a suspensionor dispersion of said coating material in a conventional coating pan orfluidized bed equipment (such as a Wurster or Glatt) followed by dryingof cores. Alternatively, said coating materials may also be applied bypowder-coating, wherein the cores are maintained in a sticky state, amixture of coating material is added continuously or periodically so asto adhere to the sticky cores, followed by drying of coated cores whendesired coating is achieved.

The “inert core” as used herein, refers to a pharmaceutically acceptableinert substrate which is routinely used in formulation art, thatincludes, but not limited to, powder or a multiparticulate such as agranule, a pellet, a bead, a spherule, a beadlet, a microcapsule, amillisphere, a nanocapsule, a nanosphere, a microsphere or a minitablet,which comprises at least one pharmaceutically acceptable excipientselected from the group comprising of water soluble, water insoluble,water swellable or water non swellable material such as starch, sugar,microcrystalline cellulose, vegetable gums, waxes, and the like.

The inert cores may also be prepared with the techniques known to aperson skilled in the art, such as, wet granulation, dry granulation, orextrusion-spheronization and the like. The inert cores have a size ofdiameter in the range of about 125 to about 600 microns.

Suitable solvent(s) used in the preparation of minocycline solution areselected from, but not limited to, water, methanol, ethanol, n-propanol,isopropanol, dichloromethane, acetone, absolute alcohol and the like ormixtures thereof.

Suitable examples of binder(s) that may be used in the presentapplication include, but are not limited to, methyl cellulose, hydroxypropyl cellulose, hydroxy propyl methyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, propylene glycol, pre gelatinizedstarch, oxide such as polyethylene oxide and the like or mixturesthereof. The binders may be combination of two or more, such as hydroxypropyl cellulose and hydroxy propyl methyl cellulose. The binders usedin the present application have a viscosity from about 5 centipoise toabout 15 centipoise.

In an aspect of the above embodiments, the binder(s) may be combinationof hydroxy propyl cellulose and hydroxy propyl methyl cellulose, presentin a ratio of from about 55:45 to about 75:25.

The amount of binders that may be used in the present application rangesfrom about 4% to about 10% by weight of the tablet.

The “loading efficiency” as used herein, refers to the binding affinityof the drug i.e. minocycline, towards inert core during a process oflayering of minocycline over the inert cores to prepare tablets, and canbe expressed herein as a percentage.

In an embodiment, the present application relates to a process ofpreparing once daily oral tablet of minocycline, comprising the stepsof: (i) preparing an immediate release (IR) portion; (ii) preparing anextended release (ER) portion; (iii) combining the IR and ER portionswith one or more one or more cushioning agent(s); and (iv) compressingthe mixture of (iii) into a tablet, wherein said process providesloading efficiency of minocycline for the IR and/or ER portions of atleast about 95%.

In another embodiment, the present application relates to a process ofpreparing once daily oral tablet of minocycline, comprising the stepsof: (i) preparing an immediate release (IR) portion comprising about 20to about 40 percent of minocycline; (ii) preparing an extended release(ER) portion comprising about 80 to about 60 percent of minocycline;(iii) combining the IR and ER portions with one or more one or morecushioning agent(s); and (iv) compressing the mixture of (iii) into atablet, wherein said process provides loading efficiency of minocyclinefor the IR and/or ER portions of at least about 95%.

In another embodiment, the present application relates to a process ofpreparing once daily oral tablet of minocycline, comprising the stepsof: (i) preparing an immediate release (IR) portion comprising about 18mg to about 66 mg of minocycline; (ii) preparing an extended release(ER) portion comprising about 54 mg to about 132 mg of minocycline;(iii) combining the IR and ER portions with one or more one or morecushioning agent(s); and (iv) compressing the mixture of (iii) into atablet, wherein said process provides loading efficiency of minocyclinefor the IR and/or ER portions of at least about 95%.

In an aspect of the above embodiments, the process of coating orlayering of minocycline and one or more binder(s) over the inert cores,provides loading efficiency of minocycline for the IR and/or ER portionsof at least about 65%, 70%, 75%, 80%, 85%, 90% or 95%.

In an aspect of the above embodiments, suitable cushioning agents thatmay be used in the present application include, but are not limited to,microcrystalline cellulose, silicified microcrystalline cellulose,calcium phosphate, mannitol, sorbitol, polyethylene glycol, sodiumstearyl fumarate, magnesium stearate, starch, talc and the like ormixtures thereof.

In an aspect of the above embodiments, the amount of cushioning agentsthat may be used in the present application ranges from about 40% toabout 60% by weight of the tablet.

In another aspect of the above embodiments, the extended release (ER)portion are prepared by coating the immediate release (IR) portion withone or more release modifying polymers.

In another aspect of the above embodiments, the present applicationrelates to a process of preparing once daily tablet of minocyclinecomprising extended release (ER) portion, wherein the ER coating layerhas a thickness of not more than 200 μm.

Suitable examples of release modifying polymers that may be used in thepresent application include, but are not limited to, unsubstituted alkylcelluloses or cellulose ethers like ethyl cellulose; and substitutedalkyl celluloses or cellulose ethers like hydroxy alkyl celluloses andcarboxy alkyl celluloses such as hydroxy ethyl cellulose, hydroxy propylcellulose, hydroxy propyl methyl cellulose, carboxy methyl ethylcellulose and carboxy methyl cellulose; acrylic and methacrylic acidpolymers and copolymers such as methyl methacrylate, ethoxy ethylmethacrylates, ethyl acrylate, amino alkyl methacrylate copolymer,poly(acrylic acid), poly(methacrylic acid), polyacrylamide and glycidylmethacrylate copolymers; polyalkylene oxides such as polyethylene oxideand polypropylene oxide and copolymers of ethylene oxide and propyleneoxide; poly vinyl alcohols, gums, synthetic resins and the like ormixtures thereof.

In an aspect of the above embodiments, the release modifying polymersmay be a combination of unsubstituted and substituted alkyl cellulosesor cellulose ethers, present in a ratio of from about 65:35 to about85:15.

In an aspect of the above embodiments, the release modifying polymersmay be a combination of unsubstituted alkyl celluloses or celluloseethers like ethyl cellulose and substituted alkyl celluloses orcellulose ethers like hydroxy propyl methyl cellulose, present in aratio of from about 65:35 to about 85:15.

The amount of release modifying polymers that may be used in the presentapplication ranges from about 5% to about 10% by weight of the tablet.

In yet another aspect of the above embodiments, the immediate release(IR) portion of minocycline tablets of the present application,comprising minocycline layered inert cores, may further optionally haveone or more barrier coating layers over said immediate release (IR)portions. Coating of barrier layer may be done by any conventionalmethods known in the art.

In yet another aspect of the above embodiments, the extended release(ER) portion of minocycline tablets of the present application,comprising immediate release (IR) portions of minocycline with one ormore layers of release modifying polymers, may further optionally haveone or more barrier coating layers over the extended release (ER)portion. Coating of barrier layer may be done by any conventionalmethods known in the art.

In yet another aspect of the above embodiments, the barrier coatinglayer over immediate release (IR) portions or extended release (ER)portions include polymers selected from the group comprising, but notlimited to, cellulose derivatives like methyl cellulose, carboxy methylcellulose, hydroxy propyl cellulose or hydroxy propyl methyl cellulose;polyethylene glycol, starch and the like or mixtures thereof.

The amount of barrier coating polymers that may be used in the presentapplication ranges from about 5% to about 10% by weight of the tablet.

In yet another aspect of the above embodiments, the barrier coatedimmediate release (IR) portion of minocycline tablets of the presentapplication, comprising minocycline layered inert cores, may furtheroptionally have one or more top or seal coating layers over saidimmediate release (IR) portions. Coating of top or seal layer may bedone by any conventional methods known in the art.

In yet another aspect of the above embodiments, the barrier coatedextended release (ER) portion of minocycline tablets of the presentapplication, comprising immediate release (IR) portions of minocyclinewith one or more layers of release modifying polymers, may furtheroptionally have one or more top or seal coating layers over the extendedrelease (ER) portion. Coating of top or seal layer may be done by anyconventional methods known in the art.

In yet another aspect of the above embodiments, the top or seal coatinglayer over barrier coated immediate release (IR) portions or extendedrelease (ER) portions include polymers selected from the groupcomprising, but not limited to, cellulose derivatives like methylcellulose, carboxy methyl cellulose, hydroxy propyl cellulose or hydroxypropyl methyl cellulose; polyethylene glycol, starch and the like ormixtures thereof.

The amount of top or seal coating polymers that may be used in thepresent application ranges from about 5% to about 10% by weight of thetablet.

In yet another aspect of the above embodiments, the minocycline tabletsof the present application provides tablets having appropriate hardness,friability and tensile strength (force required to break the tablet)that will withstand the subsequent packaging. Also the tablets offeruniformity of drug content, such that when the tablet can be dividedinto equal portions, it provides a required fractional dose.

In yet another aspect of the above embodiments, the present applicationrelates to a process of preparing tablet of minocycline, wherein saidtablet has hardness of about 25 to about 40 kilopascal and friability isless than 1%.

In another embodiment, the tablet of minocycline of present applicationmay comprises one or more pharmaceutically acceptable excipient(s)selected from lubricants, glidants, anti-tacking agents, plasticizers,disintegrants or opacifying agents and the like or mixtures thereof.

The lubricant, glidant or anti-tacking agent may be used interchangeablyin the composition of the present application and are selected from, butnot limited to, metallic stearates such as magnesium stearate, calciumstearate, zinc stearate; stearic acid, hydrogenated vegetable oil,hydrogenated castor oil, glyceryl palmitostearate, glyceryl behenate,polyethylene glycols, corn starch, sodium stearyl fumarate, sodiumbenzoate, mineral oil, talc, colloidal silicon dioxide, magnesiumtrisilicate, powdered cellulose, starch, tribasic calcium phosphate andthe like or mixtures thereof. The amount of such agents may range fromabout 0.1% w/w to about 10% w/w of the tablet.

The plasticizer used in the composition of the present application maybe used in the coating layer to increase the flexibility and strength ofthe coat/layer, and suitable plasticizer may be selected from, but notlimited to, propylene glycol, polyethylene glycol, triethyl citrate,acetyl triethyl citrate, diethyl phthalate, dibutyl phthalate, dibutylsebacate, tributyl citrate or mixtures thereof. The plasticizer may bepresent in amounts ranging from about 0.1% to about 20% w/w of thetablet.

The disintegrant used in the composition of the present application maybe selected from, but not limited to, crospovidone, sodium starchglycolate, croscarmellose sodium, croscarmellose potassium,croscarmellose calcium, carboxymethylcellulose, pregelatinized starch,carboxymethyl starch and the like or mixtures thereof. The disintegrantmay be present in amount from 1% to 20% by weight of the tablet.

In an embodiment, the present application relates to a once daily oraltablet of minocycline, wherein said tablet comprises (i) an immediaterelease (IR) portion, (ii) an extended release (ER) portion, and (iii)one or more cushioning agent(s), wherein said immediate release (IR) andextended release (ER) portions are present in a ratio of about 20:80 toabout 40:60 and said immediate release (IR) and extended release (ER)portions are present with said cushioning agent(s) present in a ratio offrom about 40:60 to about 50:50.

In another embodiment, the present application relates to a once dailyoral tablet of minocycline, wherein said tablet comprises (i) about 20to about 40 percent of minocycline in an immediate release (IR) portion(ii) about 80 to about 60 percent of minocycline in an extended release(ER) portion comprising said IR portion, and (iii) one or morecushioning agent(s), wherein said immediate release (IR) and extendedrelease (ER) portions are present in a ratio of about 20:80 to about40:60 and said immediate release (IR) and extended release (ER) portionsare present with said cushioning agent(s) present in a ratio of fromabout 40:60 to about 50:50.

In another embodiment, the present application relates to a once dailyoral tablet of minocycline, wherein said tablet comprises (i) about 20to about 40 percent of minocycline in an immediate release (IR) portion(ii) about 80 to about 60 percent of minocycline in an extended release(ER) portion comprising said IR portion, and (iii) one or morecushioning agent(s), wherein said immediate release (IR) and extendedrelease (ER) portions are present in a ratio of about 20:80 to about40:60 and said immediate release (IR) and extended release (ER) portionsare present with said cushioning agent(s) present in a ratio of fromabout 40:60 to about 50:50 and said tablet exhibit at least one of thefollowing dissolution profile when measured in USP type I apparatus at100 rpm in 900 ml of simulated gastric fluid with a pH of 2.1 and at 37°C.: about 15% to about 25% of minocycline in 15 minutes, about 35% toabout 50% of minocycline in 30 minutes, about 50% to about 65% ofminocycline in 60 minutes, and about 70% to about 90% of minocycline in120 minutes.

In an aspect of the above embodiments, said immediate release (IR)portion of the present tablet comprises hydroxy propyl cellulose andhydroxy propyl methyl cellulose present in a ratio of from about 55:45to about 75:25.

In an aspect of the above embodiments, said extended release (ER)portion of the present tablet comprises ethyl cellulose and hydroxypropyl methyl cellulose present in a ratio of from about 65:35 to about85:15.

In an embodiment, the present application relates to a method of orallyadministering once daily tablet of minocycline, wherein said tablet isdispensed in a suitable tablet storage container with a storage meansfor storing and dispensing intact tablets and/or subunits of any dividedtablets.

In another embodiment, the present application relates to a method oftreating acne in a subject comprising orally administering once dailytablet of minocycline, wherein said tablet is dispensed in a suitabletablet storage container with a storage means for storing and dispensingintact tablets and/or subunits of any divided tablets.

In an aspect of above embodiment, the tablet storage container comprisesany suitable packaging material known in the art that can ensure thestability of the minocycline during storage and in transit.

In one aspect, compositions defined in various embodiments of thepresent application are substantially free of lactose.

In another aspect, compositions applied in methods defined in severalembodiments of the present application are substantially free oflactose.

In another aspect, compositions defined in various embodiments of thepresent application are administered to a subject for a method oftreating acne.

The “stock keeping unit” or “SKU” as used herein, refers to individualdosage form package unit or container, containing single strength ofdrug.

The “inventory” as used herein, refers to minocycline dosage units thata firm or person holds in stock with the intent of selling,distributing, administering or transforming it into a more valuablestate.

The “inventory optimization” as used herein, refers to improve inventoryfor SKU comprising the present tablets of minocycline, which includesvarious inventory optimization benefits like, but are not limited to,improved cash flow by reducing inventory maintenance and occupancycosts, reduced pharmacy time spent to manage purchasing and inventoryfunctions, improved visibility to inventory management performance,educating buyer on the financial impact of purchasing and inventorymanagement, decreased expired medication waste, reduced storage spaceoccupied for said tablets of minocycline and the like, and saidinventory optimization provides at least 50% reduced SKU in a pharmacyor warehouse.

The term “shared inventory” as used herein, refers to supply of thepresent tablets of minocycline, wherein said supply includes carryinginventory comprising multiple minocycline strengths in a single tabletpackaged in a single container, which aims to reduce at least 50% totalcost of supply chain and its maintenance by providing reduced Inventorylot size and storage space in a pharmacy or warehouse.

In an embodiment, the present application relates to a once daily oraltablet of minocycline comprising, 90 mg, 105 mg, 115 mg, 135 mg or 165mg of minocycline, wherein said tablet is supplied to a pharmacy orstored in a warehouse to provide at least 50% reduced stock keepingunits for said strengths of minocycline.

In another embodiment, the present application relates to a once dailyoral tablet of minocycline comprising, 90 mg, 105 mg, 115 mg, 135 mg or165 mg of minocycline, wherein said tablet provides a shared inventoryby providing at least 50% reduced supply cost as well as storage,maintenance, and occupancy cost in a pharmacy or warehouse for saidtablets of minocycline.

In an aspect of the above embodiments, the tablet of the presentapplication comprising, 90 mg, 105 mg, 115 mg, 135 mg or 165 mg ofminocycline provides inventory optimization to a pharmacy or a warehousefor said strengths of minocycline.

In an aspect of the above embodiments, the tablet of the presentapplication comprising 90 mg of minocycline provides inventoryoptimization to a pharmacy or a warehouse by providing 45 mg or 90 mgstrengths of minocycline in scored tablets.

In an aspect of the above embodiments, the tablet of the presentapplication comprising 105 mg of minocycline provides inventoryoptimization to a pharmacy or a warehouse by providing 35 mg, 52.5 mg or105 mg strengths of minocycline in scored tablets.

In an aspect of the above embodiments, the tablet of the presentapplication comprising 115 mg of minocycline provides inventoryoptimization to a pharmacy or a warehouse by providing 57.5 mg or 115 mgstrengths of minocycline in scored tablets.

In an aspect of the above embodiments, the tablet of the presentapplication comprising 135 mg of minocycline provides inventoryoptimization to a pharmacy or a warehouse by providing 45 mg, 67.5 mg or135 mg strengths of minocycline in scored tablets.

In an aspect of the above embodiments, the tablet of the presentapplication comprising 165 mg of minocycline provides inventoryoptimization to a pharmacy or a warehouse by providing 55 mg, 82.5 mg or165 mg strengths of minocycline in scored tablets. In an aspect of theabove embodiments, the present tablet provides minocycline dose ofapproximately 1 mg/kg body weight.

In an aspect of the above embodiments, the present tablet is dispensedto a subject for treating acne.

In an aspect of the above embodiments, the present tablet is dispensedas intact or by dividing into two or more equal subunits.

In an embodiment, the present application relates to a once daily oraltablet of minocycline comprising 90 mg, 105 mg, 115 mg, 135 mg or 165 mgof minocycline, wherein said tablet is supplied to a pharmacy orwarehouse in a suitable tablet storage container with a storage meansfor storing and dispensing intact tablets and/or subunits of any dividedtablets.

In another embodiment, the present application relates to a once dailyoral tablet of minocycline comprising 90 mg, 105 mg, 115 mg, 135 mg or165 mg of minocycline, wherein said tablet is dispensed to a subject fortreating acne in a suitable tablet storage container with a storagemeans for storing and dispensing intact tablets and/or subunits of anydivided tablets.

In an aspect of above embodiment, the tablet storage container comprisesany suitable packaging material known in the art that can ensure thestability of the minocycline during storage and in transit.

In an embodiment, the present application relates to a once daily oraltablet of minocycline comprises of 35 mg, 45 mg, 52.5 mg, 55 mg, 57.5mg, 67.5 mg, 70 mg, 82.5 mg, 90 mg, 105 mg, 110 mg, 115 mg, 135 mg or165 mg of minocycline and one or more pharmaceutically acceptableexcipient(s).

In another embodiment, the present application relates to a method oftreating acne in a patient comprising orally administering thecomposition of minocycline.

In an embodiment, the present application relates to a method oftreating acne in a patient comprising orally administering a once dailyoral tablet of minocycline comprises of 35 mg, 45 mg, 52.5 mg, 55 mg,57.5 mg, 67.5 mg, 70 mg, 82.5 mg, 90 mg, 105 mg, 110 mg, 115 mg, 135 mgor 165 mg of minocycline.

In another embodiment, the present application relates to a compositionof minocycline, comprising minocycline and one or more pharmaceuticallyacceptable excipient(s), comprising (i) about 20 to about 40 percent ofminocycline in an immediate release (IR) portion and (ii) about 80 toabout 60 percent of minocycline in an extended release (ER) portion andsaid tablet exhibits at least one of the following dissolution profilewhen measured in USP type I apparatus at 100 rpm in 900 ml of simulatedgastric fluid with a pH of 2.1 and at 37° C.: about 15% to about 25% ofminocycline in 15 minutes, about 35% to about 50% of minocycline in 30minutes, about 50% to about 65% of minocycline in 60 minutes, and about70% to about 90% of minocycline in 120 minutes.

In another embodiment, the present application relates to a compositionof minocycline, comprising minocycline and one or more pharmaceuticallyacceptable excipient(s), comprising (i) about 20 to about 40 percent ofminocycline in an immediate release (IR) portion and (ii) about 80 toabout 60 percent of minocycline in an extended release (ER) portion andsaid tablet exhibits at least one of the following dissolution profilewhen measured in USP type I apparatus at 100 rpm in 900 ml of acetatebuffer with a pH of 4.5 and at 37° C.: about 15% to about 25% ofminocycline in 15 minutes, about 35% to about 45% of minocycline in 30minutes, about 50% to about 65% of minocycline in 60 minutes, and about70% to about 90% of minocycline in 120 minutes.

In another embodiment, the present application relates to a compositionof minocycline, comprising minocycline and one or more pharmaceuticallyacceptable excipient(s), comprising (i) about 20 to about 40 percent ofminocycline in an immediate release (IR) portion and (ii) about 80 toabout 60 percent of minocycline in an extended release (ER) portion andsaid tablet exhibits at least one of the following dissolution profilewhen measured in USP type I apparatus at 100 rpm in 900 ml of phosphatebuffer with a pH of 5.5 and at 37° C.: about 15% to about 25% ofminocycline in 15 minutes, about 35% to about 45% of minocycline in 30minutes, about 50% to about 65% of minocycline in 60 minutes, and about70% to about 90% of minocycline in 120 minutes.

The present application is further illustrated by the examples which areprovided merely to be exemplary of the pharmaceutical compositiondescribed above and do not limit the scope of the application. Certainmodifications and equivalents will be apparent to those skilled in theart and are intended to be included within the scope of the presentapplication.

The present invention is illustrated below by reference to the followingexamples. However, one skilled in the art will appreciate that thespecific methods and results discussed are merely illustrative of thepresent invention, and not to be construed as limiting the application.The following examples may include compilations of data that arerepresentative of data gathered at various times during the course ofdevelopment and experimentation related to the present invention.

EXAMPLES Examples 1-3

The tablets of the present application comprising minocycline areprepared as described herein.

TABLE 1 Quantity per unit (%) Composition Ex-1 Ex - 2 Ex - 3 Ex - 4 Drugloading Inert core 14.86 13 12.66 13 Minocycline Hydrochloride 15.812.67 13.46 12.67 (equivalent to Minocycline 135 mg) Hydroxy propylcellulose 3.45 3.45 3.45 3.45 Hydroxy propyl methyl cellulose 1.80 1.851.85 1.85 Polyethylene glycol 400 0.52 0.69 0.67 0.69 Talc 0.79 1.821.77 1.82 Water qs to 15.7% w/w qs qs qs qs Total 37.22 33.53 33.7133.53 Barrier coating Hydroxy propyl methyl cellulose 1.86 1.67 1.681.67 Polyethylene glycol 400 0.18 0.16 0.16 0.16 Talc 0.55 0.50 0.500.50 Water qs qs qs qs Total 2.59 2.34 2.35 2.34 Extended releasecoating Ethyl cellulose 5.43 4.69 3.93 4.69 Hydroxy propyl methylcellulose 1.81 1.56 1.31 1.56 Triethyl citrate 0.54 0.46 0.39 0.46 Talc2.17 1.87 1.57 1.87 Isopropyl alcohol qs qs qs qs Water qs qs qs qsTotal 9.95 8.60 7.2 8.60 Outer top coating Hydroxy propyl methylcellulose 5.34 3.80 3.86 3.80 Polyethylene glycol 400 0.53 0.38 0.380.38 Talc 1.60 1.13 1.16 1.13 Water qs qs qs qs Total 7.47 5.32 5.4 5.32Top coating to barrier coating Hydroxy propyl methyl cellulose — — 0.77— Polyethylene glycol 400 — — 0.07 — Talc — — 0.23 — Water — — qs —Total — — 1.07 — Compression stage Outer top coated portions + 53.749.81 49.81 49.81 Barrier coated portions/Top coating to barrier coatedportions Silicified microcrystalline 41.24 44.83 44.83 44.83 celluloseMicrocrystalline cellulose 4.58 4.98 4.98 4.98 Sodium stearyl fumarate0.37 0.37 0.37 0.37 Total weight 100 100 100 100

Procedure:

-   -   a. Drug solution is prepared by dissolving minocycline, hydroxy        propyl methyl cellulose, hydroxy propyl cellulose, polyethylene        glycol and talc in water and layered onto inert core.    -   b. Barrier coating solution is prepared by dissolving hydroxy        propyl methyl cellulose, followed by adding polyethylene glycol        and talc with stirring.    -   c. Extended release coating solution is prepared by dissolving        the required amount of ethyl cellulose and hydroxy propyl methyl        cellulose in isopropyl alcohol, followed by adding triethyl        cellulose.    -   d. Outer top or seal coating solution is prepared similarly as        barrier coating solution.    -   e. Immediate release (IR) portion is prepared by coating barrier        coating solution as prepared in step (b) onto drug loaded        portion of step (a) and optionally followed by top or seal        coating.    -   f. Extended release (ER) portion is prepared by coating extended        release solution as prepared in step (c) onto drug loaded        portion of step (a) followed by outer top or seal coating.    -   g. For examples 1, 3 & 4 accurately weighed amount of silicified        microcrystalline cellulose, microcrystalline cellulose and        sodium stearyl fumarate were blended with 20 percent of IR        portions and 80 percent of ER portions and compressed into        tablets with a single score.    -   h. For example 2, accurately weighed amount of silicified        microcrystalline cellulose, microcrystalline cellulose and        sodium stearyl fumarate were blended with 25 percent of IR        portions and 75 percent of ER portions and compressed into        tablets with a single score.    -   i. Compressed tablets of step (g) or (h) were packaged in a        suitable pharmaceutical tablet storage bottle.

Example 5

The tablet comprising minocycline as prepared in example 4 was subjectedto content uniformity studies as intact tablet and after dividing intotwo equal subunits. The results are shown in table 2.

TABLE 2 Intact Assay % - Example 4 No. of units Intact tablet Division 1Division 2 1 101 99 95 2 99 102 95 3 97 101 93 4 97 103 93 5 96 103 93 698 101 93 7 99 99 92 8 98 99 91 9 99 99 94 10 99 102 92 Mean 98.5 101 93Acceptance 3.8 4 8.7 Value % Relative 1.51 1.66 1.44 standard deviationResult Pass Pass Pass

Example 6

The tablet comprising minocycline as prepared in example 2 was subjectedto dissolution studies in 900 ml of pH 2.1 Simulated Gastric Fluid, pH4.5 acetate buffer and pH 5.5 phosphate buffer with USP Type I apparatusat a speed of 100 rpm and 37° C. till 6 hours and the in-vitro releaseprofile are shown in FIGS. 1, 2 and 3 respectively.

Example 7

The tablet comprising minocycline as prepared in example 4 was subjectedto disintegration studies in water and 1 table spoon of apple sauce, andresults are given in table 3.

TABLE 3 Disintegration time Assay (%) Apple After 1 hr with Water sauceInitial apple sauce 35-40 sec 14-17 min 101.3 99.6

Example 8

The pharmacokinetic parameters for minocycline tablets of the presentapplication, was studied in comparison with SOLODYN® (80 mg+55 mg) oraltablets by using a two-way crossover method. The study was conducted in77 healthy human subjects, in fasting and fed conditions and thesubjects were administered a single dose of composition of Example 2equivalent to 135 mg of minocycline. The results are shown in Table 4and the mean plasma minocycline concentration vs. time profile forfasting and fed conditions vis-a-vis SOLODYN® is shown in FIGS. 4A and4B.

TABLE 4 SOLODYN ® Example 2 (80 mg ± 55 mg) Fasting Fed Fasting FedParameters conditions conditions conditions conditions C_(max) (ng/mL) 700 ± 261  707 ± 190  657 ± 230  750 ± 208 T_(max) (hr) 2.01 3.50 4.005.00 t_(1/2) (hr)  15.6 ± 2.46  17.1 ± 3.03  15.6 ± 2.62  17.6 ± 4.42AUC_((0-t)) 10900 ± 3720 12000 ± 2970 11000 ± 3480 12900 ± 2820 (ng ·hr/mL) AUC_((0-∞)) 11400 ± 3890 12700 ± 3340 11600 ± 3690 13700 ± 3540(ng · hr/mL)

While several particular forms of the application have been illustratedand described, it will be apparent that various modifications andcombinations of the application detailed in the text can be made withoutdeparting from the spirit and scope of the application.

What is claimed is:
 1. A method of treating acne in a patient in needthereof comprising orally administering once daily to the patient awhole or half a tablet comprising minocycline hydrochloride equivalentto 105 mg or 135 mg of minocycline, where the tablet consistsessentially of (i) immediate release pellets comprising (a) an inertcore, (b) a drug layer comprising minocycline hydrochloride on the inertcore, and (c) a barrier coating layer; (ii) extended release pelletscomprising (a) an inert core, (b) a drug layer comprising minocyclinehydrochloride on the inert core, and (c) a coating with one or morerelease modifying polymers to provide extended release of theminocycline hydrochloride in the drug layer of the extended releasepellets; and (iii) one or more cushioning agents to prevent adhesion ofthe pellets during compression, wherein the minocycline hydrochloride isthe sole active ingredient in the tablet, about 20 to about 40 percentof the minocycline hydrochloride present in the tablet is present in theimmediate release pellets and about 80 to about 60 percent of theminocycline hydrochloride present in the tablet is present in theextended release pellets, and the tablet has one score line for dividingthe tablet into equal subunits to provide a predictable and accuratedose of minocycline, where (i) the divided subunits have uniformity ofdrug content and (ii) the divided subunits and the intact tablet exhibitsimilar dissolution profiles when measured in a USP type I apparatus at100 rpm in 900 ml of simulated gastric fluid with a pH of 2.1 and at 37°C.
 2. The method of claim 1, wherein the tablet is substantially free oflactose.
 3. The method of claim 1, wherein the inert cores of theimmediate release pellets and the inert cores of the extended releasepellets comprise microcrystalline cellulose.
 4. The method of claim 1,wherein the inert cores of the immediate release pellets and the inertcores of the extended release pellets have a diameter of 125 to 600microns.
 5. The method of claim 1, wherein the barrier coating comprisesone or more polymers selected from methyl cellulose, carboxy methylcellulose, hydroxy propyl cellulose, hydroxy propyl methyl cellulose,polyethylene glycol, starch, and any combination of any of theforegoing.
 6. The method of claim 1, wherein the one or more releasemodifying polymers consist essentially of ethyl cellulose and hydroxypropyl methyl cellulose.
 7. The method of claim 6, wherein the weightratio of ethyl cellulose to hydroxy propyl methyl cellulose is from65:35 to 85:15.
 8. The method of claim 7, wherein the one or morerelease modifying polymers are present in an amount of 5% to 10% byweight of the tablet.
 9. The method of claim 1, wherein the coating onthe extended release pellets consists essentially of ethyl cellulose,hydroxy propyl methyl cellulose, and a plasticizer.
 10. The method ofclaim 9, wherein the plasticizer is triethyl citrate.
 11. The method ofclaim 1, wherein the only minocycline hydrochloride in the immediaterelease pellets is in the drug layer of the immediate release pellets,and the only minocycline hydrochloride in the extended release pelletsis in the drug layer of the extended release pellets.
 12. The method ofclaim 1, wherein the one or more cushioning agents are selected frommicrocrystalline cellulose, silicified microcrystalline cellulose,calcium phosphate, mannitol, sorbitol, polyethylene glycol, sodiumstearyl fumarate, magnesium stearate, starch, talc, or any combinationof any of the foregoing.
 13. The method of claim 1, wherein the amountof cushioning agent(s) in the tablet ranges from 40% to 60% by weight,based upon 100% total weight of the tablet.
 14. The method of claim 1,wherein the patient suffers from inflammatory lesions of non-nodularmoderate to severe acne vulgaris.
 15. A method of treating acne in apatient having a body weight of 45 to 59 kg comprising: (a) dividing ascored tablet containing minocycline hydrochloride equivalent to 105 mgof minocycline along the score line into two equal subunits, and (b)orally administering to the patient one subunit of the tablet oncedaily, wherein the tablet consists essentially of (i) immediate releasepellets comprising (a) an inert core, (b) a drug layer comprisingminocycline hydrochloride on the inert core, and (c) a barrier coatinglayer; (ii) extended release pellets comprising (a) an inert core, (b) adrug layer comprising minocycline hydrochloride on the inert core, and(c) a coating with one or more release modifying polymers to provideextended release of the minocycline hydrochloride in the drug layer ofthe extended release pellets; and (iii) one or more cushioning agents toprevent adhesion of the pellets during compression, wherein theminocycline hydrochloride is the sole active ingredient in the tablet,about 20 to about 40 percent of the minocycline hydrochloride present inthe tablet is present in the immediate release pellets and about 80 toabout 60 percent of the minocycline hydrochloride present in the tabletis present in the extended release pellets, and the tablet has one scoreline for dividing the tablet into equal subunits to provide apredictable and accurate dose of minocycline, where (i) the dividedsubunits have uniformity of drug content and (ii) the divided subunitsand the intact tablet exhibit similar dissolution profiles when measuredin a USP type I apparatus at 100 rpm in 900 ml of simulated gastricfluid with a pH of 2.1 and at 37° C.
 16. A method of treating acne in apatient having a body weight of 60 to 84 kg comprising: (a) dividing ascored tablet containing minocycline hydrochloride equivalent to 135 mgof minocycline along the score line into two equal subunits, and (b)orally administering to the patient one subunit of the tablet oncedaily, wherein the tablet consists essentially of (i) immediate releasepellets comprising (a) an inert core, (b) a drug layer comprisingminocycline hydrochloride on the inert core, and (c) a barrier coatinglayer; (ii) extended release pellets comprising (a) an inert core, (b) adrug layer comprising minocycline hydrochloride on the inert core, and(c) a coating with one or more release modifying polymers to provideextended release of the minocycline hydrochloride in the drug layer ofthe extended release pellets; and (iii) one or more cushioning agents toprevent adhesion of the pellets during compression, wherein theminocycline hydrochloride is the sole active ingredient in the tablet,about 20 to about 40 percent of the minocycline hydrochloride present inthe tablet is present in the immediate release pellets and about 80 toabout 60 percent of the minocycline hydrochloride present in the tabletis present in the extended release pellets, and the tablet has one scoreline for dividing the tablet into equal subunits to provide apredictable and accurate dose of minocycline, where (i) the dividedsubunits have uniformity of drug content and (ii) the divided subunitsand the intact tablet exhibit similar dissolution profiles when measuredin a USP type I apparatus at 100 rpm in 900 ml of simulated gastricfluid with a pH of 2.1 and at 37° C.